Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the general formula (I) 
                         
wherein Z is a template-fixed chain of 12, 14 or 18 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, NMeGly, Pro or Pip, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have CXCR4 antagonizing properties These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. application Ser. No. 12/828,998 which is a divisional application of U.S. application Ser. No. 10/555,088, issued as U.S. Pat. No. 7,786,078 filed on Oct. 31, 2005 and afforded a §371 date of Dec. 16, 2005, which U.S. application Ser. No. 10/555,088 is the National Stage filing in the U.S. of International Application No. PCT/EP2004/004535, filed Apr. 29, 2004, which claims priority to PCT/EP03/04640, filed May 2, 2003, the entire contents of all which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention provides template-fixed βhairpin peptidomimetics incorporating template-fixed chains of 12, 14 or 18 α-amino acid residues which, depending on their positions in the chains, are Gly, NMeGly, Pro or Pip, or of certain types, as defined hereinbelow. These template-fixed β-hairpin mimetics have CXCR4 antagonizing activity. In addition, the present invention provides an efficient synthetic process by which these compounds can, if desired, be made in parallel library-format. These β-hairpin peptidomimetics show improved efficacy, bioavailability, half-life and most importantly a significantly enhanced ratio between CXCR4 antagonizing activity on the one hand, and hemolysis on red blood cells and cytotoxicity on the other.

BACKGROUND OF THE INVENTION

To date the available therapies for the treatment of HIV infections have been leading to a remarkable improvement in symptoms and recovery from disease in infected people. Although the highly active anti retroviral therapy (HAART-therapy) which involves a combination of reverse transcriptase/protease inhibitor has dramatically improved the clinical treatment of individuals with AIDS or HIV infection there have still remained several serious problems including multi drug resistance, significant adverse effects and high costs. Particularly desired are anti HIV agents that block the HIV infection at an early stage of the infection, such as the viral entry.

It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require the chemokine receptors CCR5 and CXCR4 as well as the primary receptor CD4 (N. Levy, Engl. J. Med., 335, 29, 1528-1530). Accordingly, an agent which could block the CXCR4 chemokine receptors should prevent infections in healthy individuals and slow or halt viral progression in infected patients (Science, 1997, 275, 1261-1264).

Among the different types of CXCR4 inhibitors (M. Schwarz, T. N. C. Wells, A. E. I. Proudfoot, Receptors and Channels, 2001, 7, 417-428), one emerging class is based on naturally occurring cationic peptide analogues derived from Polyphemusin II which have an antiparallel 3-sheet structure, and a β-hairpin that is maintained by two disulfide bridges (H. Nakashima, M. Masuda, T. Murakami, Y. Koyanagi, A. Matsumoto, N. Fujii, N. Yamamoto, Antimicrobial Agents and Chemoth. 1992, 36, 1249-1255; H. Tamamura, M. Kuroda, M. Masuda, A. Otaka, S. Funakoshi, H. Nakashima, N. Yamamoto, M. Waki, A. Matsumotu, J. M. Lancelin, D. Kohda, S. Tate, F. Inagaki, N. Fujii, Biochim. Biophys. Acta 1993, 209, 1163; WO 95/10534 A1).

Synthesis of structural analogs and structural studies by nuclear magnetic resonance (NMR) spectroscopy have shown that the cationic peptides adopt well defined β-hairpins conformations, due to the constraining effect of the one or two disulfide bridges (H. Tamamura, M. Sugioka, Y. Odagaki, A. Omagari, Y. Kahn, S. Oishi, H. Nakashima, N. Yamamoto, S. C. Peiper, N. Hamanaka, A. Otaka, N. Fujii, Bioorg. Med. Chem. Lett. 2001, 359-362). These results show that the β-hairpin structure plays an important role in CXCR4 antagonizing activity.

Additional structural studies have also indicated that the antagonizing activity can also be influenced by modulating amphiphilic structure and the pharmacophore (H. Tamamura, A. Omagari, K. Hiramatsu, K. Gotoh, T. Kanamoto, Y. Xu, E. Kodama, M. Matsuoka, T. Hattori, N. Yamamoto, H. Nakashima, A. Otaka, N. Fujii, Bioorg. Med. Chem. Lett. 2001, 11, 1897-1902; H. Tamamura, A. Omagari, K. Hiramatsu, S. Oishi, H. Habashita, T. Kanamoto, K. Gotoh, N. Yamamoto, H. Nakashima, A. Otaka N. Fujii, Bioorg. Med. Chem. 2002, 10, 1417-1426; H. Tamamura, K. Hiramatsu, K. Miyamoto, A. Omagari, S. Oishi, H. Nakashima, N. Yamamoto, Y. Kuroda, T. Nakagawa, A. Otaki, N. Fujii, Bioorg. Med. Chem. Letters 2002, 12, 923-928).

A key issue in the design of CXCR4 antagonizing peptides is selectivity. The polyphemusin II derived analogs exert still a cytotoxicity despite improvements (K. Matsuzaki, M. Fukui, N. Fujii, K. Miyajima, Biochim. Biophys. Acta 1991, 259, 1070; A. Otaka, H. Tamamura, Y. Terakawa, M. Masuda, T. Koide, T. Murakami, H. Nakashima, K. Matsuzaki, K. Miyajima, T. Ibuka, M. Waki, A. Matsumoto, N. Yamamoto, N. Fujii Biol. Pharm. Bull. 1994, 17, 1669 and cited references above).

This cytotoxic activity essentially obviates its use in vivo, and represents a serious disadvantage in clinical applications. Before intravenous use can be considered, the general toxicity, protein-binding activity in blood serum, as well as protease stability become serious issues which must be adequately addressed.

Recently, it has been shown that the CXCR4-receptor is not only involved in the entry of HIV but also in the chemotactic activity of cancer cells, such as breast cancer metastasis or in metastasis of ovarian cancer (A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M. E. Buchanan, T. Mc Clanahan, E. Murphey, W. Yuan, S. N. Wagner, J. Luis Barrera, A. Mohar, E. Verastegui, A. Zlotnik, Nature 2001, 50, 410, J. M. Hall, K. S. Korach, Molecular Endocrinology, 2003, 1-47), Non-Hodgin's Lymphoma (F. Bertolini, C. DellAgnola, P. Manusco, C. Rabascio, A. Burlini, S. Monestiroli, A. Gobbi, G. Pruneri, G. Martinelli, Cancer Research 2002, 62, 3106-3112), or lung cancer (T. Kijima, G. Maulik, P. C. Ma, E. V. Tibaldi, R: E. Turner, B. Rollins, M. Sattler, B. E. Johnson, R. Salgia, Cancer Research 2002, 62, 6304-6311), melanoma, prostate cancer, kidney cancer, neuroblastomia, pancreatic cancer, multiple myeloma, chronic lymphocytic leukemia (H. Tamamura et al. Febs Letters 2003, 550 79-83, cited ref.) Blocking the chemotactic activity with a CXCR4 inhibitor should stop the migration of cancer cells.

The CXCR4 receptor has also been implicated in the growth and proliferation of tumors. It was shown that activation of the CXCR4 receptor was critical for the growth of both malignant neuronal and glial tumors, and small cell lung tumors. Moreover, systemic administration of the CXCR4 antagonist AMD3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells (Rubin J B, Kung A L, Klein R S, Chan J A, Sun Y, Schmidt K, Kieran M W, Luster A D, Segal R A. Proc Natl Acad Sci USA. 2003 100(23):13513-13518, Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti J L, Zona C L, Spaziante R, Florio T, Schettini G. Stromal Cancer Res. 2003, 63(8):1969-1974, Kijima T, Maulik G, Ma P C, Tibaldi E V, Turner R E, Rollins B, Sattler M, Johnson B E, Salgia R. Cancer Res. 2002; 62(21):6304-631 1, Cancer Res. 2002; 62(11):3106-3112.

The chemokine stromal cell-derived factor-1 (CXCL12/SDF-1) and its receptor CXCR4 are involved in trafficking of B cells and hematopoietic progenitors. It has been shown that the CXCR4 receptor plays an important role in the release of stem cells from the bone marrow to the peripheral blood. The receptor is for instance expressed on CD34+ cells, and has been implicated in the process of CD34+ cell migration and homing. This activity of the CXCR4 receptor could be very important for efficient apheresis collections of peripheral blood stem cell. Autologous peripheral blood cells provide a rapid and sustained hematopoietic recovery following autotransplantation after the administration of high-dose chemotherapy or radiotherapy in patients with haematological malignancies and solid tumors. (W C. Liles et al, Blood 2003, 102, 2728-2730).

There is increasing evidence that suggests that chemokines in general and the interaction between the chemoattractant CXCL12/stromal cell-derived factor-I alpha and its receptor CXCR4 in particular play a pivotal role in angiogenesis. Chemokines induce angiogenesis directly by binding their cognate receptors on endothelial cells or indirectly by promoting inflammatory cell infiltrates, which deliver other angiogenic stimuli. A number of proinflammatory chemokines including interleukin 8 (IL-8), growth-regulated oncogene, stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1), eotaxin 1, and I-309 have been shown to act as direct inducers of angiogenesis. (Chen X, Beutler J A, McCloud T G, Loehfelm A, Yang L, Dong H F, Chertov O Y, Salcedo R, Oppenheim J J, Howard O M. Clin Cancer Res. 2003 9(8):3115-3123, Salcedo R, Oppenheim J J. Microcirculation 2003 (3-4):359-370)

It is well established that chemokines are involved in a number of inflammatory pathologies and some of them show a pivotal role in the modulation of osteoclast development. Immunostaining for SDF-1 (CXCL12) on synovial and bone tissue biopsies from both rheumatoid arthritis (RA) and osteoarthritis (OA) samples have revealed strong increases in the expression levels under inflammatory conditions. (Grassi F, Cristino S, Toneguzzi S, Piacentini A, Facchini A, Lisignoli G. J Cell Physiol. 2004; 199(2):244-251. It seems likely that the CXCR4 receptor plays an important role in inflammatory diseases e.g. such as rheumatoid arthritis, asthma, or multiple sclerose (K. R. Shadidi et al, Scandinavian Journal of Immunology, 2003, 57, 192-198, J. A. Gonzalo J Immunol. 2000, 165, 499-508, S. Hatse et al, FEBS Letters 2002 527, 255-262 and cited references).

The mediation of recruitment of immune cells to sites of inflammation should be stopped by a CXCR4 inhibitor.

In the compounds described below, a new strategy is introduced to stabilize beta-hairpin conformations in cyclic backbone-turn peptidomimetics exhibiting high CXCR4 antagonizing activity, being useful for efficient apheresis collections of peripheral blood stem cells, and having anticancer activity and anti inflammatory activity.

This involves transplanting the cationic and hydrophobic hairpin sequence onto a template, whose function is to restrain the peptide loop backbone into a hairpin geometry. The rigidity of the hairpin may be further influenced by introducing a disulfide bridge. Template-bound hairpin mimetic peptides have been described in the literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem. 1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), but such molecules have not previously been evaluated for development of CXCR4 antagonizing peptides. However, the ability to generate β-hairpin peptidomimetics using combinatorial and parallel synthesis methods has now been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112).

These methods allow the synthesis and screening of large hairpin mimetic libraries, which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with highly potent CXCR4 antagonizing activity or anti cancer activity or anti inflammatory activity and low hemolytic activity to human red blood cells. β-Hairpin peptidomimetics obtained by the approach described here are useful as Anti-HIV agents, anticancer agents, as inhibitors of tumor growth or as apoptosis inducing agents, anti-metastasis agents, and anti inflammatory agents or as agents that can be used in apheresis collections of peripheral blood stem cells. The β-hairpin peptidomimetics can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells. The β-hairpin peptidomimetics can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells.

SUMMARY OF THE INVENTION

The β-hairpin peptidomimetics of the present invention are compounds of the general formula

is a group of one of the formulae

is Gly or the residue of an L-α-amino acid with B being a residue of formula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69 as defined hereinafter;

is a group of one of the formulae

-   -   R¹ is H; lower alkyl; or aryl-lower alkyl;     -   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵—;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;         aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹),         NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;     -   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(C₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;         —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;         —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or         —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹¹ is H—; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰ ₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁴;         —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(o)CONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(q)(CHR⁶¹)_(s)SOR²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)OR⁵⁵;         —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)₅PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or     -   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;     -   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(o)CONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸SR⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)SOR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(r)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCoNR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or     -   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;         —(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or         —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;     -   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;         —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹) SO₂R⁶²; or         —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;     -   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰ ₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³² is H; lower alkyl; or aryl-lower alkyl;     -   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;     -   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; (CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴, —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;         —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁸ is H; F; Br, Cl; NO₂; CF₃; alkyl; alkenyl;         —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;     -   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;     -   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;         —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹) NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;         —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)NR²⁰CONR³³R⁸²;         —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;         —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or         —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(o)(CHR⁶¹)₂SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR)₂;         —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;         —(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;     -   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;     -   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;     -   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;         (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²;         or —(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;     -   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶²)_(p)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;         —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶¹; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;     -   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;         —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHRR⁶¹)_(s)C₆H₄R⁸;     -   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;         —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;         —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;     -   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;         —(CH₂)_(m)(CHR⁶¹)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;         —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;         —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;         or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹,     -   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or         heteroaryl lower alkyl;     -   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;         aryl-lower alkyl; or heteroaryl-lower alkyl;     -   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;         aryl-lower alkyl; or heteroaryl-lower alkyl; or     -   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;     -   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;         heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;         —(CH₂)_(m)OCONR⁷⁵R⁸²; —(CH₂)_(m)NR²⁰CONR⁷⁵R⁸²; —(CH₂)_(o)COOR³⁷;         —(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂;     -   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or         aryl-lower alkyl;     -   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl;         aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷;         —CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂     -   R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;         aryl-lower alkyl; heteroaryl-lower alkyl;         —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or         —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;         —(CH₂)_(p)(CHR⁶¹)NR²CONR⁷⁸R⁸²;     -   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;         heteroaryl-lower alkyl; —COR¹⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;     -   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;         heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;     -   m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or         1;     -   Z is a chain of n α-amino acid residues, n being the integer 12,         14 or 18 and the positions of said amino acid residues in said         chain being counted starting from the N-terminal amino acid,         whereby these amino acid residues are, depending on their         position in the chains, Gly, NMeGly, Pro or Pip, or of formula         -A-CO—, or of formula —B—CO—, or of one of the types     -   C: —NR²⁰CH(R⁷²)CO—;     -   D: —NR²⁰CH(R⁷³)CO—;     -   E: —NR²⁰CH(R⁷⁴)CO—;     -   F: —NR²⁰CH(R⁸⁴)CO—; and     -   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;         —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;         —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and         —NR²⁰—CH(CO—)-(—CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;     -   I: —NR⁸⁶CH₂CO—;     -   R⁷¹ is lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;         —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;         —(CH₂)_(p)(CHR⁶¹)₅OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)N²⁰CONR³³R⁸²;         —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹;         —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or         —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;     -   R⁷² is H, lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵;         or —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;     -   R⁷³ is —(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;         —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;     -   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;         —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;         —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;         —(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;         —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;         —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;         —(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;         —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(m)N═(NR⁷⁸R⁷⁹)NR⁷⁹R⁸⁰;         —(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;         —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;         —(CH₂)_(p)NR⁸⁰COR⁶⁴; —(CH₂)_(p)NR⁸⁰COR⁷⁷;         —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or         —(CH₂)_(p)NR²⁰CO—[(CH₂)_(u)—X]_(t)—CH₃ where X is —O—; —NR²⁰—,         or —S—; u is 1-3, and t is 1-6;     -   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl;     -   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;         —(CH₂)_(o)R⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;         —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵,         —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or         —(CH₂)_(o)COR⁶⁴;     -   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the         formulae

-   -   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;     -   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or     -   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—;         or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁸⁰ is H; or lower alkyl;     -   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;     -   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;     -   R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;     -   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;     -   R⁸⁴ is —(CH₂)_(m)(CHR₆₁)_(s)OH; —(CH₂)pCOOR₈₀;         —(CH₂)_(m)(CHR₆₁)_(s)SH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;         —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or         —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;     -   R⁸⁵ is lower alkyl; or lower alkenyl;     -   R⁸⁶ is R⁷⁴; —(CH₂)_(o)R⁷⁷; —(CH₂)_(o)—CHR³³R⁷⁵; or         —[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)NR⁷⁸R⁷⁹; or         —[(CH₂)_(u)—X′]_(t)—(CH₂)_(v)—(═NR⁸⁰)NR⁷⁸R⁷⁹ where X is —O—,         —NR²⁰—, —S—; or —OCOO—, u is 1-3, t is 1-6, and v is 1-3;     -   with the proviso that in said chain of n α-amino acid residues Z         -   if n is 12, the amino acid residues in positions 1 to 12             are:             -   P1: of type C or of type D or of type E or of type F, or                 the residue is Pro or Pip;             -   P2: of type E, or of type F or the residue is Gly,                 NMeGly, Pro or Pip;             -   P3; or of type E, of type F;             -   P4: of type C, or of type D, or of type F, or the                 residue is Gly or NMeGly;             -   P5: of type E, or of type D, or of type C, or of type F,                 or of formula -A-CO— or the residue is Gly. NMeGly, Pro                 or Pip;             -   P6: of type E, or of type F, or of formula —B—CO—, or                 the residue is Gly or NMeGly;             -   P7: of type C, or of type E or of type F;             -   P8: of type D, or of type C, or the residue is Pro or                 Pip;             -   P9: of type C, or of type D or of type F, or the residue                 is Gly or NMeGly;             -   P10: of type D, or of type C, or the residue is Pro or                 Pip;             -   P11: of type E or of type F or the residue is Gly or                 NMeGly; and             -   P12: of type C or of type D or of type E or of type F,                 or the residue is Pro or Pip; or             -   P4 and P9 and/or P2 and P11, taken together, can form a                 group of type H;         -   at P4, P6. P9 also D-isomers being possible; and         -   if n is 14, the amino acid residues in positions 1 to 14             are:             -   P1: of type C, or of type D, or of type E, or of type F,                 or the residue is Gly or NMeGly or Pro or Pip;             -   P2: of type E, or of type F, or of type I, or of type D;             -   P3: of type E, or of type F; or of type D, or of type C,                 or the residue is Gly, NMeGly, Pro Pip;             -   P4: of type D, or of type C or of type F, or of type E;             -   P5: of type E, or of type F, or of type C or of type I;             -   P6: of type C, or of type D, or of type F, or the                 residue is Gly, NMeGly, Pro or Pip;             -   P7: of type C, or of type D, or of formula A-CO—, or the                 residue is Gly, NMeGly. Pro Pip;             -   P8: of type E, or of Type F, or of formula B—CO— or of                 type I, or of type D, or the residue is Pro Pip;             -   P9: of type F, or of type E, or of type I, or of type D,                 or the residue is Pro or Pip;             -   P10: of type F, or of type D, or of type C;             -   P11: of type D, or of type C, or of type F, or of type                 E, or the residue is Pro or Pip;             -   P12: of type C, or of type D, or of type E, or of type                 F;             -   P13: of type F, or of type E, or the residue is Gly.                 NMeGly, Pro or Pip; and             -   P14; or of type F or of type E or of type C; or             -   P2 and P13 and/or P4 and P11, take together, can form a                 group of type H;         -   at P4, P7, P8 and P11 D-isomers being possible;         -   with the further proviso that             -   the amino acid residue in P1 is Gly or NMeGly or Pip;                 and/or             -   the amino acid residue in P2 is of type F or of type I;                 and/or             -   the amino acid residue in P3 is of type F, or it is Gly,                 NMeGly. Pro or Pip;         -   and/or             -   the amino acid residue in P4 is of type F; and/or             -   the amino acid residue in P5 is of type C or of type F                 or of type 1; and/or             -   the amino acid residue in P6 is of type C or of type D,                 or it is Gly or NMeGly;         -   and/or             -   the amino acid residue in P7 is of type C or of type D,                 or it is Pro. Pip or NMeGly; and/or             -   the amino acid residue in P8 is of type I or of type D,                 or it is Pro or Pip; and/or             -   the amino acid residue in P9 is of type F or of type I,                 or it is Pip; and/or             -   the amino acid residue in P10 is of type F; and/or             -   the amino acid residue in P11 is of type C, or it is                 Pip; and/or             -   the amino acid residue in P12 is of type C or of type F;                 and/or             -   the amino acid residue in P13 is of type F, or it is                 Gly, NMeGly or Pip; and/or             -   P2 and P13, taken together, form a group of type H;                 and/or             -   P4 and P11, taken together, form a group of type H;                 and/or             -   the amino acid residue in P4 is a D-isomer, and/or             -   the amino acid residue in P11 is a D-isomer, and         -   if n is 18, the amino acid residues in positions 1 to 18             are:             -   P1: of type D, or of type E, or of type C, or of type F;             -   P2: of type E, or of type F, or of type D;             -   P3: of type C, or of type D;             -   P4: of type E, or of type D, or of type F;             -   P5: of type D, or of type C, or of type E;             -   P6: of type C, or of type E, or of type F;             -   P7: of type C, or of type D, or of type E or of type F;             -   P8: of type F, or of type E, or the residue is Gly or                 NMeGly;             -   P9: of type C, or of type D, or of type F;             -   P10: of type C, or of type E, or of formula -A-CO—, or                 the residue is Pro or Pip;             -   P11: of type C, or of type E, or of formula —B—CO—, or                 the residue is Gly, NMeGly, Pro or Pip;             -   P12: of type D, or of type C, or type F;             -   P13: of type E, or of type F, or the residue is Gly or                 NMeGly;             -   P14: of type C, or of type D, or of type F;             -   P15: of type E, or of type F;             -   P16: of type D, or of type E, or of type F;             -   P17: of type E, or of type F; and             -   P18: of type C, or of type D, or of type E, or of type                 F; or             -   P4 and P17 and/or P6 and P15 and/or P8 and P13, taken                 together, can form a group of type H;         -   at P10, P11 and P12 also D-isomers being possible;         -   and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention these β-hairpin peptidomimetics can be prepared by a process which comprises

-   -   (a) coupling an appropriately functionalized solid support with         an appropriately N-protected derivative of that amino acid which         in the desired end-product is in position 5, 6 or 7 if n is 12,         or which in the desired end-product is in position 6, 7 or 8 if         n is 14, or which in the desired end-product is in position 8, 9         or 10 if n is 18, any functional group which may be present in         said N-protected amino acid derivative being likewise         appropriately protected;     -   (b) removing the N-protecting group from the product thus         obtained;     -   (c) coupling the product thus obtained with an appropriately         N-protected derivative of that amino acid which in the desired         end-product is one position nearer the N-terminal amino acid         residue, any functional group which may be present in said         N-protected amino acid derivative being likewise appropriately         protected;     -   (d) removing the N-protecting group from the product thus         obtained;     -   (e) repeating steps (c) and (d) until the N-terminal amino acid         residue has been introduced;     -   (f) coupling the product thus obtained with a compound of the         general formula

is as defined above and X is an N-protecting group or, alternatively, if

-   -   is to be group (a1) or (a2), above,         -   (fa) coupling the product obtained in step (e) with an             appropriately N-protected derivative of an amino acid of the             general formula             HOOC—B—H  III             or             HOOC-A-H  IV     -   wherein B and A are as defined above, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;         -   (fb) removing the N-protecting group from the product thus             obtained; and         -   (fc) coupling the product thus obtained with an             appropriately N-protected derivative of an amino acid of the             above general formula IV and, respectively, III, any             functional group which may be present in said N-protected             amino acid derivative being likewise appropriately             protected; and, respectively, if

-   -   is to be group (a3), above,         -   (fa′) coupling the product obtained in step (e) with an             appropriately N-protected derivative of an amino acid of the             above general formula III, any functional group which may be             present in said N-protected amino acid derivative being             likewise appropriately protected;         -   (fb′) removing the N-protecting group from the product thus             obtained; and         -   (fc′) coupling the product thus obtained with an             appropriately N-protected derivative of an amino acid of the             above general formula III, any functional group which may be             present in said N-protected amino acid derivative being             likewise appropriately protected;     -   (g) removing the N-protecting group from the product obtained in         step (f) or (fc) or (fc′);     -   (h) coupling the product thus obtained with an appropriately         N-protected derivative of that amino acid which in the desired         end-product is in position 12 if n is 12, or in position 14 if n         is 14, or in position 18 if n is 18, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;     -   (i) removing the N-protecting group from the product thus         obtained;     -   (j) coupling the product thus obtained with an appropriately         N-protected derivative of that amino acid which in the desired         end-product is one position farther away from position 12 if n         is 12 or in position 14 if n is 14, or from position 18 if n is         18, any functional group which may be present in said         N-protected amino acid derivative being likewise appropriately         protected;     -   (k) removing the N-protecting group from the product thus         obtained;     -   (l) repeating steps (j) and (k) until all amino acid residues         have been introduced;     -   (m) if desired, selectively deprotecting one or several         protected functional group(s) present in the molecule and         appropriately substituting the reactive group(s) thus liberated;     -   (n) if desired, forming one, two or three interstrand linkage(s)         between side-chains of appropriate amino acid residues at         opposite positions of the β-strand region;     -   (o) detaching the product thus obtained from the solid support;     -   (p) cyclizing the product cleaved from the solid support;     -   (q) removing any protecting groups present on functional groups         of any members of the chain of amino acid residues and, if         desired, any protecting group(s) which may in addition be         present in the molecule; and     -   (r) if desired, converting the product thus obtained into a         pharmaceutically acceptable salt or converting a         pharmaceutically acceptable, or unacceptable, salt thus obtained         into the corresponding free compound of formula I or into a         different, pharmaceutically acceptable, salt.

Alternatively, the peptidomimetics of the present invention can be prepared by

-   -   (a′) coupling an appropriately functionalized solid support with         a compound of the general formula

is as defined above and X is an N-protecting group or, alternatively, if

-   -   is to be group (a1) or (a2), above.         -   (a′a) coupling said appropriately functionalized solid             support with an appropriately N-protected derivative of an             amino acid of the general formula             HOOC—B—H  III             or             HOOC-A-H  IV     -   wherein B and A are as defined above, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;         -   (a′b) removing the N-protecting group from the product thus             obtained; and         -   (a′c) coupling the product thus obtained with an             appropriately N-protected derivative of an amino acid of the             above general formula IV and, respectively, III, any             functional group which may be present in said N-protected             amino acid derivative being likewise appropriately             protected; and, respectively, if

-   -   is to be group (a3), above,         -   (a′a′) coupling the product obtained in step (e) with an             appropriately N-protected derivative of an amino acid of the             above general formula II, any functional group which may be             present in said N-protected amino acid derivative being             likewise appropriately protected;         -   (a′b′) removing the N-protecting group from the product thus             obtained; and         -   (a′c′) coupling the product thus obtained with an             appropriately N-protected derivative of an amino acid of the             above general formula III, any functional group which may be             present in said N-protected amino acid derivative being             likewise appropriately protected;     -   (b′) removing the N-protecting group from the product obtained         in step (a′), (a′c) or (a′c′);     -   (c′) coupling the product thus obtained with an appropriately         N-protected derivative of that amino acid which in the desired         end-product is in position 12 if n is 12, or in position 14 if n         is 14, or in position 18 if n is 18, any functional group which         may be present in said N-protected amino acid derivative being         likewise appropriately protected;     -   (d′) removing the N-protecting group from the product thus         obtained;     -   (e′) coupling the product thus obtained with an appropriately         N-protected derivative of that amino acid which in the desired         end-product is one position farther away from position 12 if n         is 12, or from position 14 if n is 14, or from position 18 if n         is 18, any functional group which may be present in said         N-protected amino acid derivative being likewise appropriately         protected;     -   (f′) removing the N-protecting group from the product thus         obtained;     -   (g′) repeating steps (e′) and (f′) until all amino acid residues         have been introduced;     -   (h′) if desired, selectively deprotecting one or several         protected functional group(s) present in the molecule and         appropriately substituting the reactive group(s) thus liberated;     -   (i′) if desired forming one, two or three interstrand linkage(s)         between side-chains of appropriate amino acid residues at         opposite positions of the β-strand region;     -   (j′) detaching the product thus obtained from the solid support;     -   (k′) cyclizing the product cleaved from the solid support;     -   (l′) removing any protecting groups present on functional groups         of any members of the chain of amino acid residues and, if         desired, any protecting group(s) which may in addition be         present in the molecule; and     -   (m′) if desired, converting the product thus obtained into a         pharmaceutically acceptable salt or converting a         pharmaceutically acceptable, or unacceptable, salt thus obtained         into the corresponding free compound of formula I or into a         different, pharmaceutically acceptable, salt.

Introducing an amino acid residue of type I can, alternatively, be effected by coupling with a leaving group-containing acylating agent, such as bromo, chloro or iodo acetic acid, followed by nucleophilic displacement with an amine of the formula H₂N—R⁸⁶ which, if necessary, is appropriately protected.

The peptidomimetics of the present invention can also be enantiomers of the compounds of formula I. These enantiomers can be prepared by a modification of the above processes in which enantiomers of all chiral starting materials are used.

As used in this description, the term “alkyl”, taken alone or in combinations, designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms. Similarly, the term “alkenyl” designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. The term “lower” designates radicals and compounds having up to 6 carbon atoms. Thus, for example, the term “lower alkyl” designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and the like. The term “aryl” designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl” designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said ring(s) being optionally substituted; representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R⁷.

The structural element -A-CO— designates amino acid building blocks which in combination with the structural element —B—CO— form templates (a1) and (a2). The structural element —B—CO— forms in combination with another structural element —B—CO— template (a3). Preferably template (a3) is present only in formula I wherein n is 18 in chain Z. Templates (a) through (p) constitute building blocks which have an N-terminus and a C-terminus oriented in space in such a way that the distance between those two groups may lie between 4.0-5.5 A. A peptide chain Z is linked to the C-terminus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termini so that the template and the chain form a cyclic structure such as that depicted in formula I. In a case as here where the distance between the N- and C-termini of the template lies between 4.0-5.5 A the template will induce the H-bond network necessary for the formation of a β-hairpin conformation in the peptide chain Z. Thus template and peptide chain form a β-hairpin mimetic.

The β-hairpin conformation is highly relevant for the CXCR4 antagonizing activity of the β-hairpin mimetics of the present invention. The β-hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for the selective CXCR4 antagonizing activity but also for the synthesis process defined hereinabove, as incorporation of the templates at the beginning or near the middle of the linear protected peptide precursors enhances cyclization yields significantly.

Building blocks A1-A69 belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring. Among the genetically encoded amino acids only proline falls into this class. The configuration of building block A1 through A69 is (D), and they are combined with a building block —B—CO— of (L)-configuration. Preferred combinations for templates (a1) are -^(D)A1-CO—^(L)B—CO— to ^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes the prototype of templates (a1). Less preferred, but possible are combinations -^(L)A1-CO—^(D)B—CO— to ^(L)A69-CO—^(D)B—CO— forming templates (a2). Thus, for example, ^(L)Pro-^(D)Pro constitutes the prototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in which A has (D)-configuration, are carrying a group R¹ at the α-position to the N-terminus. The preferred values for R¹ are H and lower alkyl with the most preferred values for R¹ being H and methyl. It will be recognized by those skilled in the art, that A1-A69 are shown in (D)-configuration which, for R¹ being H and methyl, corresponds to the (R)-configuration. Depending on the priority of other values for R¹ according to the Cahn, Ingold and Prelog-rules, this configuration may also have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry an additional substituent designated as R² to R¹⁷. This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group. Examples of preferred values for R² to R⁷ are:

-   -   R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl);         (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower         alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;         or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³         and R⁸² taken together from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where         R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;         or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR⁸² (where R²⁰: H; or lower lower alkyl; R³³:         H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or         R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where         R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or         R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower         alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl);         (CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:         H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or         R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: alkyl; alkenyl; aryl; and aryl-lower alkyl;         heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower         alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower         alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and         R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkenyl; or lower alkoxy).     -   R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² where R²⁰: H; or lower lower alkyl; R³³:         H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or         R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁹R⁵⁹ (where         R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;         or F⁵⁸ and R⁵⁹ taken together from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower         alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         (CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:         H; or lower alkyl; or lower alkyl; R⁸²: H; or lower alkyl; or         R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where         R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;         or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); (CH₂)rSO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵         (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where         R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         from: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together from:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower         alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶ (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R⁶⁴         (where: R²⁰: H; lower alkyl; R⁶⁴: lower alkyl; or lower         alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower         alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower         alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken         together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³⁴: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl); or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl;         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or         lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly         favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower alkyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)₂OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸²) where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷; lower alkyl;         alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Most preferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3); diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6); methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10); n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13); n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl (A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); and n-nonyl (A8′-20).

Building block A70 belongs to the class of open-chain α-substituted α-amino acids, building blocks A71 and A72 to the corresponding 1-amino acid analogues and building blocks A73-A104 to the cyclic analogues of A70. Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (C. M. Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander, Biopolymers 1983, 22, 2577). Such building blocks or templates are ideally suited for the stabilization of β-hairpin conformations in peptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv. Med. Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids in peptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992, 2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P. Balaram, “β-turn conformations in crystal structures of model peptides containing α,α-disubstituted amino acids”. Biopolymers 1995, 35, 1-9; V. J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— to A104-CO— in combination with a building block —B—CO— of L-configuration can efficiently stabilize and induce β-hairpin conformations (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv. Med. Chem. 1999, Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Miller, H. Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D. Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller, Tetrahedron 1995, 51, 10883-10900: D. Obrecht, C. Lehmann, C. Ruffieux, P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schinholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can also consist of -A70-CO— to A104-CO— where building block A70 to A104 is of either (D)- or (L)-configuration, in combination with a building block —B—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methyl being most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹-R²⁹ in building blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.     -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         (CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸⁷ (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         particularly favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower         alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower         alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower         alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy);     -   R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         particularly favoured are NR²⁰CO lower alkyl (R²⁰ ═H; or lower         alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower         alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower         alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy);     -   R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)CONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;         —(CH₂)₂O (CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl).     -   R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂N⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂; —; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S((CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         particularly favored are NR²⁰CO lower-alkyl (R²⁰═H; or lower         alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower         alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower         alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).

For templates (b) to (p), such as (b1) and (c1), the preferred values for the various symbols are the following:

-   -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵         (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶         (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴         (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower         alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or         lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower         alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or         lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R²⁰: H; or lower alkyl.     -   R³⁰: H, methyl.     -   R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         (—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy); most preferred is 13 CH₂CONR⁵⁸R⁵⁹         (R⁵⁸: H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).     -   R³²: H, methyl.     -   R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴:         lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴         and R⁶³ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); (CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵: lower alkyl; or lower         alkenyl; R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together         form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl;         R⁷⁸: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R⁷⁸ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).     -   R³⁴: H; or lower alkyl.     -   R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R²⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).     -   R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.     -   R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆−; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;         or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³         and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH)_(o)CONR⁵⁸R⁵⁹ (where         R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or         R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R³⁸: H; lower alkyl; lower alkenyl; —(CH)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl;         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where:         R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).     -   R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.     -   R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);         —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or         —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² where R²⁰: H; or lower lower alkyl; R³³:         H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or         R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;         R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where         R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where         R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or         R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower         alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower         alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower         alkyl; lower alkenyl; or lower alkoxy).     -   R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower         alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower         alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴         taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(s)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).     -   R⁴⁸: H; or lower alkyl.     -   R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl;         or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl;         or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken         together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁵⁰: H; methyl.     -   R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H;         or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower         alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷         (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹         (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower         alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F;         Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).     -   R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:         lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:         lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³         and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;         —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower         alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or         lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together         form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);         —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;         R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower         alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;         —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where         R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;         or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);         —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);         —(CH₂)_(p)CONR⁵⁸R⁵⁸ (where R⁵⁸: lower alkyl; or lower alkenyl;         and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:         —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or         —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or         —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower         alkenyl; or lower alkoxy).     -   R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Among the building blocks A70 to A104 the following are preferred: A74 with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within templates (a1), (a2) and (a3) designates an L-amino acid residue. Preferred values for B are: —NR²⁰CH(R⁷¹)— and enantiomers of groups A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Most preferred are

-   Ala L-Alanine -   Arg L-Arginine -   Asn L-Asparagine -   Cys L-Cysteine -   Gln L-Glutamine -   Gly Glycine -   His L-Histidine -   Ile L-Isoleucine -   Leu L-Leucine -   Lys L-Lysine -   Met L-Methionine -   Phe L-Phenylalanine -   Pro L-Proline -   Ser L-Serine -   Thr L-Threonine -   Trp L-Tryptophan -   Tyr L-Tyrosine -   Val L-Valine -   Cit L-Citrulline -   Orn L-Ornithine -   tBuA L-t-Butylalanine -   Sar Sarcosine -   t-BuG L-tert-Butylglycine -   4AmPhe L-para-Aminophenylalanine -   3AnPhe L-meta-Aminophenylalanine -   2AmPhe L-ortho-Aminophenylalanine -   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine -   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine -   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine -   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine -   Phg L-Phenylglycine -   Cha L-Cyclohexylalanine -   C₄al L-3-Cyclobutylalanine -   C₅al L-3-Cyclopentylalanine -   Nle L-Norleucine -   2-Nal L-2-Naphthylalanine -   1-Nal L-1-Naphthylalanine -   4Cl-Phe L-4-Chlorophenylalanine -   3Cl-Phe L-3-Chlorophenylalanine -   2Cl-Phe L-2-Chlorophenylalanine -   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine -   4F-Phe L-4-Fluorophenylalanine -   3F-Phe L-3-Fluorophenylalanine -   2F-Phe L-2-Fluorophenylalanine -   Tic L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid -   Thi L-β-2-Thienylalanine -   Tza L-2-Thiazolylalanine -   Mso L-Methionine sulfoxide -   AcLys L-N-Acetyllysine -   Dpr L-2,3-Diaminopropionic acid -   A₂Bu L-2,4-Diaminobutyric acid -   Dbu (S)-2,3-Diaminobutyric acid -   Abu γ-Aminobutyric acid (GABA) -   Aba ε-Aminohexanoic acid -   Aib α-Aminoisobutyric acid -   Y(Bzl) L-O-Benzyltyrosine -   Bip L-Biphenylalanine -   S(Bzl) L-O-Benzylserine -   T(Bzl) L-O-Benzylthreonine -   hCha L-Homo-cyclohexylalamine -   hCys L-Homo-cysteine -   hSer L-Homo-serine -   hArg L-Homo-arginine -   hPhe L-Homo-phenylalanine -   Bpa L-4-Benzoylphenylalanine -   Pip L-Pipecolic acid -   OctG L-Octylglycine -   MePhe L-N-Methylphenylalanine -   MeNle L-N-Methylnorleucine -   MeAla L-N-Methylalanine -   MeIle L-N-Methylisoleucine -   MeVal L-N-Methyaline -   MeLeu L-N-Methylleucine

In addition, the most preferred values for B also include groups of type A8″ of (L)-configuration:

-   -   wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;         —[(CH₂)₂u-X]_(t)—CH₃ (where X is —O—; —NR²⁰—, or —S—; u=1-3, and         t=1-6), aryl; aryl-lower alkyl; or heteroaryl-lower alkyl;         especially those wherein R⁶⁴ is n-hexyl (A8″-21); n-heptyl         (A8″-22); 4-(phenyl)benzyl (A8″-23); diphenylmethyl (A8″-24);         3-amino-propyl (A8″-25); 5-amino-pentyl (A8″-26); methyl         (A8″-27); ethyl (A8″¹-28); isopropyl (A8″-29); isobutyl         (A8″-30); n-propyl (A8″-31); cyclohexyl (A8″-32);         cyclohexylmethyl (A8″-33); n-butyl (A8″-34); phenyl (A8″-35);         benzyl (A8″-36); (3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl         (A8″-38); (4-phenyl)phenyl (A8″-39); n-nonyl (A8″-40);         CH₃—OCH₂CH₂—OCH₂— (A8″-41) and CH₃—(OCH₂CH₂)₂—OCH₂— (A8″-42).

The peptidic chain Z of the β-hairpin mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following groups:

-   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized” -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or     heteroaromatic” -   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived” -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic” -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;     —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰;     —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and     —NR²⁰—CH(CO—)-(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;     “interstrand linkage” -   Group I —NR⁸⁶CH₂CO—; “polar-cationic or hydrophobic”

Furthermore, the amino acid residues in chain Z can also be of formula -A-CO— or of formula —B—CO— wherein A and B are as defined above. Finally, Gly can also be an amino acid residue in chain Z, and Pro can be an amino acid residue in chain Z, too, with the exception of positions where interstrand linkages (H) are possible.

Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substituent R⁷². A hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution. Furthermore these side chains generally do not contain hydrogen bond donor groups, such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. However, they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates or tertiary amines. Genetically encoded small-to-medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substituent R⁷³. An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated π-electron system (aromatic group). In addition they may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates- and phosphates or tertiary amines. Genetically encoded aromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated n-system incorporating at least one heteroatom such as (but not limited to) O, S and N according to the general definition for substituent R⁷⁷. In addition such residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates- and phosphates or tertiary amines. Genetically encoded heteroaromatic amino acids include tryptophan and histidine.

Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea-derived residues according to the general definition for substituent R⁷⁴. Polar-cationic refers to a basic side chain which is protonated at physiological pH. Genetically encoded polar-cationic amino acids include arginine, lysine and histidine. Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains with polar-non-charged or anionic residues according to the general definition for substituent R⁸⁴. A polar-non-charged or anionic residue refers to a hydrophilic side chain that is uncharged and, respectively anionic at physiological pH (carboxylic acids being included), but that is not repelled by aqueous solutions. Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, carboxyclic acids and esters, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. These groups can form hydrogen bond networks with water molecules. In addition they may also contain hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, carboxylic acids and carboxylates, alkyl- or aryl phosphonates- and phosphates or tertiary amines. Genetically encoded polar-non-charged amino acids include asparagine, cysteine, glutamine, serine and threonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at opposite positions of the β-strand region that can form an interstrand linkage. The most widely known linkage is the disulfide bridge formed by cysteines and homo-cysteines positioned at opposite positions of the β-strand. Various methods are known to form disulfide linkages including those described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart et al., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company, Ill., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; and Pennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds., ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scope of the present invention, disulfide linkages can be prepared using acetamidomethyl (Acm)-protective groups for cysteine. A well established interstrand linkage consists in linking ornithines and lysines, respectively, with glutamic and aspartic acid residues located at opposite β-strand positions by means of an amide bond formation. Preferred protective groups for the side chain amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic and glutamic acid. Finally, interstrand linkages can also be established by linking the amino groups of lysine and ornithine located at opposite β-strand positions with reagents such as N,N-carbonylimidazole to form cyclic ureas.

Group I comprises glycine having the amino group substituted by chains containing polar-cationic or hydrophobic residues according to the general definition for substituent R⁸⁶. Polar-cationic refers to a basic side chain which is protonated at physiological pH. A hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution.

As mentioned earlier, positions for interstrand linkages are, if n is 12, positions P4 and P9; and/or P2 and P11 taken together; if n is 14, positions P2 and P13 and/or P4 and P11; and, if n is 18, positions P4 and P17 and/or P6 and P15 and/or P8 and P13 taken together. Such interstrand linkages are known to stabilize the β-hairpin conformations and thus constitute an important structural element for the design of β-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived from natural α-amino acids. Hereinafter follows a list of amino acids which, or the residues of which, are suitable for the purposes of the present invention, the abbreviations corresponding to generally adopted usual practice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R Asn L-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamic acid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H Ile L-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M Phe L-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine S Thr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Other α-amino acids which, or the residues of which, are suitable for the purposes of the present invention include:

-   Cit L-Citrulline -   Orn L-Ornithine -   tBuA L-t-Butylalanine -   Sar Sarcosine -   Pen L-Penicillamine -   t-BuG L-tert.-Butylglycine -   4AmPhe L-para-Aminophenylalanine -   3AmPhe L-meta-Aminophenylalanine -   2AmPhe L-ortho-Aminophenylalanine -   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine -   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine -   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine -   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine -   Phg L-Phenylglycine -   Cha L-Cyclohexylalanine -   C₄al L-3-Cyclobutylalanine -   C₅al L-3-Cyclopentylalanine -   Nle L-Norleucine -   2-Nal L-2-Naphthylalanine -   1-Nal L-1-Naphthylalanine -   4Cl-Phe L-4-Chlorophenylalanine -   3Cl-Phe L-3-Chlorophenylalanine -   2Cl-Phe L-2-Chlorophenylalanine -   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine -   4F-Phe L-4-Fluorophenylalanine -   3F-Phe L-3-Fluorophenylalanine -   2F-Phe L-2-Fluorophenylalanine -   Tic 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid -   Thi L-β-2-Thienylalanine -   Tza L-2-Thiazolylalanine -   Mso L-Methionine sulfoxide -   AcLys N-Acetyllysine -   A₂Bu 2,4-Diaminobutyric acid -   Dbu (S)-2,3-Diaminobutyric acid -   Abu γ-Aminobutyric acid (GABA) -   Aha ε-Aminohexanoic acid -   Aib α-Aminoisobutyric acid -   Y(Bzl) L-O-Benzyltyrosine -   Bip L-(4-phenyl)phenylalanine -   S(Bzl) L-O-Benzylserine -   T(Bzl) L-O-Benzylthreonine -   hCha L-Homo-cyclohexylalanine -   hCys L-Homo-cysteine -   hSer L-Homo-serine -   hArg L-Homo-arginine -   hPhe L-Homo-phenylalanine -   Bpa L-4-Benzoylphenylalanine -   4-AmPyrr1 (2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid -   4-AmPyrr2 (2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid -   4-PhePyrr1 (2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid -   4-PhePyrr2 (2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid -   5-PhePyrr1 (2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid -   5-PhePyrr2 (2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid -   Pro(4-OH) 1 (4S)-L-Hydroxyproline -   Pro(4-OH)₂ (4R)-L-Hydroxyproline -   Pip L-Pipecolic acid -   ^(D)Pip D-Pipecolic acid -   OctG L-Octylglycine -   NGly N-Methylglycine -   MePhe L-N-Methylphenylalanine -   MeNle L-N-Methylnorleucine -   MeAla L-N-Methylalanine -   MeIle L-N-Methylisoleucine -   MeVal L-N-Methylvaline -   MeLeu L-N-Methylleucine -   DimK L-(N′,N′Dimethyl)-lysine -   Lpzp L-piperazinic acid -   Dpzp D-piperazinic acid -   Isom L-(N′,N′-diisobutyl)-ornithine -   PipAla L-2-(4′-piperidinyl)-alanine -   PirrAla L-2-(3′-pyrrolidinyl)-alanine -   Ampc 4-Amino-piperidine-4-carboxylic acid -   NMeR L-N-Methylarginine -   NMeK L-N-Methyllysine -   NMePhe L-N-Methylphenylalanine -   IPegK     L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic     acid -   SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)-acetylamino]-hexanoic acid -   Dab L-1,4-Diamino-butyric acid -   IPegDab     L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric     acid -   SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)-acetylamino]butyric acid -   4-PyrAla L-2-(4′Pyridyl)-alanine -   OmPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic acid -   BnG N-Benzylglycine -   (4-OH)BnG N-4-Hydroxy-benzylglycine -   IaG N-Isoamylglycine -   IbG N-Isobutlyglycine -   (EA)G N-(2-Aminoethyl)glycine -   (PrA)G N-(3-Amino-n-propyl)glycine -   (BA)G N-(4-Amino-n-butyl)glycine -   (PeA)G N-(5-Amino-n-pentyl)glycine -   (PEG₃-NH₂)G N—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine -   (Pyrr)G N-{2-[2′-(1′-methyl-pyrrolidinyl)]-ethyl}-glycine -   (Dimp)G N-[2-(N′,N′-Dimethylamino)-propyl]-glycine -   (Im)G N-[3-(1′-imidazolyl)-propyl]-glycine -   (Pip)G N-{3-[1′-(4′-methylpiperazinyl)]-propyl}-glycine -   (Dime)G N-[2-(N′,N′-Dimethylamino)-ethyl]-glycine

Particularly preferred residues for group C are:

-   Ala L-Alanine -   Ile L-Isoleucine -   Leu L-Leucine -   Met L-Methionine -   Val L-Valine -   tBuA L-t-Butylalanine -   t-BuG L-tert.-Butylglycine -   Cha L-Cyclohexylalanine -   C₄al L-3-Cyclobutylalanine -   Csal L-3-Cyclopentylalanine -   Nle L-Norleucine -   hCha L-Homo-cyclohexylalanine -   OctG L-Octylglycine -   MePhe L-N-Methylphenylalanine -   MeNle L-N-Methylnorleucine -   MeAla L-N-Methylalanine -   MeIle L-N-Methylisoleucine -   MeVal L-N-Methylvaline -   MeLeu L-N-Methylleucine

Particularly preferred residues for group D are:

-   His L-Histidine -   Phe L-Phenylalanine -   Trp L-Tryptophan -   Tyr L-Tyrosine -   Phg L-Phenylglycine

2-Nal L-2-Naphthylalanine

-   1-Nal L-1-Naphthylalanine -   4Cl-Phe L-4-Chlorophenylalanine -   3Cl-Phe L-3-Chlorophenylalanine -   2Cl-Phe L-2-Chlorophenylalanine -   3,4Cl₂-Phe L-3,4-Dichlorophenylalanine -   4F-Phe L-4-Fluorophenylalanine -   3F-Phe L-3-Fluorophenylalanine -   2F-Phe L-2-Fluorophenylalanine -   Thi L-2-Thienylalanine -   Tza L-2-Thiazolylalanine -   Y(Bzl) L-O-Benzyltyrosine -   Bip L-Biphenylalanine -   S(Bzl) L-O-Benzylserine -   T(Bzl) L-O-Benzylthreonine -   hPhe L-Homo-phenylalanine -   Bpa L-4-Benzoylphenylalanine -   PirrAla L-2-(3′-pyrrolidinyl)-alanine -   NMePhe L-N-Methylphenylalanine -   4-PyrAla L-2-(4′Pyridyl)-alanine

Particularly preferred residues for group E are

-   Arg L-Arginine -   Lys L-Lysine -   Orn L-Ornithine -   Dpr L-2,3-Diaminopropionic acid -   Dbu (S)-2,3-Diaminobutyric acid -   Phe(pNH₂) L-para-Aminophenylalanine -   Phe(mNH₂) L-meta-Aminophenylalanine -   Phe(oNH₂) L-ortho-Aminophenylalanine -   hArg L-Homo-arginine -   Phe(mC(NH₂)═NH) L-meta-Amidinophenylalanine -   Phe(pC(NH₂)═NH) L-para-Amidinophenylalanine -   Phe(mNHC(NH₂)═NH) L-meta-Guanidinophenylalanine -   Phe(pNHC(NH₂)═NH) L-para-Guanidinophenylalanine -   DimK L-(N′,N′Dimethyl)-lysine -   Isom L-(N′,N′-diisobutyl)-ornithine -   NMeR L-N-Methylarginine -   NMeK L-N-Methyllysine -   IPegK     L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic     acid -   SPegK L-2-Amino-6-[2-(2methoxy-ethoxy)-acetylamino]-hexanoic acid -   Dab L-1,4-Diamino-butyric acid -   IPegDab     L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric     acid -   SPegDab L-2-Amino-4[2-(2-methoxy-ethoxy)-acetylamino]butyric acid -   OmPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic -   PipAla L-2-(4′-piperidinyl)-alanine

Particularly preferred residues for group F are

-   Asn L-Asparagine -   Asp L-Aspartic acid -   Cys L-Cysteine -   Gln L-Glutamine -   Glu L-Glutamic acid -   Ser L-Serine -   Thr L-Threonine -   Cit L-Citrulline -   Pen L-Penicillamine -   AcLys L-N-Acetyllysine -   hCys L-Homo-cysteine -   hSer L-Homo-serine

Particularly preferred residues for group I are

-   (EA)G N-(2-Aminoethyl)glycine -   (PrA)G N-(3-Amino-n-propyl)glycine -   (BA)G N-(4-Amino-n-butyl)glycine -   (PeA)G N-(5-Amino-n-pentyl)glycine -   (EGU)G N-(2-Guanidinoethyl)glycine -   (PrGU)G N-(3-Guanidino-n-propyl)glycine -   (BGU)G N-(4-Guanidino-n-butyl)glycine -   (PeGU)G N-(5-Guanidino-n-pentyl)glycine -   (PEG₃-NH₂)G N—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine -   (Pyrr)G N-{2-[2′-(1′-methyl-pyrrolidinyl)]-ethyl}-glycine -   (Dimp)G N-[2-(N′,N′-Dimethylamino)-propyl]-glycine -   (Im)G N-[3-(1′-imidazolyl)-propyl]-glycine -   (Pip)G N-{3-[1′-(4′-methylpiperazinyl)]-propyl}-glycine -   (Dime)G N-[2-(N′,N′-Dimethylamino)-ethyl]-glycine

Generally, the peptidic chain Z within the β-hairpin mimetics of the invention comprises 12, 14 or 18 amino acid residues. The positions P1 to P12 and, respectively, to P14, or P18 of each amino acid residue in the chain Z are unequivocally defined as follows: P1 represents the first amino acid in the chain Z that is coupled with its N-terminus to the C-terminus of the templates (b)-(p), or of group —B—CO— in template (a1), or of group -A-CO— in template (a2), or of the group —B—CO— forming the C-terminus of template (a3); and P12 and, respectively, P14 or P18 represents the last amino acid in the chain Z that is coupled with its C-terminus to the N-terminus of the templates (b)-(p), or of group -A-CO— in template (a1), or of group —B—CO— in template (a2), or of the group —B—CO— forming the N-terminus of template (a3). Each of the positions P1 to P12 and, respectively, to P14 or P18 will preferably contain an amino acid residue belonging to one of the above types C D, E, F, I, H, or of formula -A-CO— or of formula —B—CO—, or being Gly, NMeGly, Pro or Pip as follows:

If n is 12 the α-amino acid residues in positions 1 to 12 of the chain Z are preferably:

P1: of type C, or of type D, or of type F, or the residue is Pro or Pip;

P2: of type E, or of type F, or the residue is Gly, NMeGly, Pro or Pip;

P3: or of type E, of type F;

P4: of type C, or of type D, or of type F, or the residue is Gly or NMeGly;

P5: of type E, or of type D, or of type F, or the residue is Gly, NMeGly, Pro or Pip;

P6: of type E, or of type F, or of formula —B—CO—, or the residue is Gly or NMeGly;

P7: of type E, or of type F;

P8: of type D, or of type C, or the residue is Pro or Pip;

P9: of type C, or of type D, or of type F, or the residue is Gly or NMeGly;

P10: of type D, or of type C, or the residue is Pro or Pip;

P11: of type E, or of type F, or the residue is Gly or NMeGly; and

P12: of type E or of type F, or the residue is Pro or Pip; or

P4 and P9, taken together, form a group of type H;

at P4, P6, P9 also D-isomers being possible.

If n is 12, the α-amino acid residues in positions 1 to 12 are most preferably:

P1: Tyr;

P2: Arg, Gly;

P3: Cit;

P4: Val, Phe, Gly, Ile, Thr, Gln, Cys;

P5: Arg;

P6: Arg, ^(D)Arg;

P7: Arg;

P8: Trp, 2-Nal;

P9: Val, Phe, Gly, Ile, Thr, Gln, Cys;

P10: Tyr;

P11: Cit, Gly; and

P12: Lys; or

Cys at P4 and P9 form a disulfide bridge.

If n is 14, the α-amino acid residues in positions 1 to 14 of the chain Z are preferably:

P1: of type C, or of type D, or of type E, or of type F, or the residue is Gly or NMeGly or Pro or Pip;

P2: of type E, or of type D, or of type F;

P3: of type E, or of type F, or of type D, or of type C, or the residue is Pro or Pip;

P4: of type D, or of type C, or of type F;

P5: of type E, or of type F, or of type I;

P6: of type C, or of type D, or of type F, or the residue is Gly, NMeGly, Pro or Pip;

P7: of type C, or of type D, or of formula -A-CO—, or the residue is Gly, NMeGly, Pro or Pip;

P8: of type E, or of Type F, or of type D, or of type I, or thr residue is Pro or Pip;

P9: of type F, or of type E, or of type D, or of type I, or the residue is Pro or Pip;

P10: of type F, or of type D, or of type C;

P11: of type D, or of type C, or of type F, or of type E;

P12: of type C, or of type D, or of type F;

P13: of type F, or of type E, or of type D, or of type C, or of type I, or the residue is Gly or NMeGly; and

P14; or of type F, or of type E, or of type C; or

P2 and P13 and/or P4 and P11, taken together, form a group of type H;

at P4, P7, P8 or P11 D-isomers being possible;

with the proviso that

the amino acid residue in P1 is Gly or NMeGly or Pip; and/or

the amino acid residue in P2 is of type F; and/or

the amino acid residue in P3 is of type F, or it is Pro or Pip; and/or

the amino acid residue in P4 is of type F; and/or

the amino acid residue in P5 is of type F, or of type I; and/or

the amino acid residue in P6 is of type C, or of type D, or it is NMeGly or Pip; and/or

the amino acid residue in P7 is of type C, or of Type D, or it is NMeGly, Pro or Pip; and/or

the amino acid residue in P8 is of type D, or of type I, or it is Pro or Pip and/or

the amino acid residue in P9 is of type F, or of type I, or it is Pip; and/or

the amino acid residue in P10 is of type F; and/or

the amino acid residue in P11 is of type C; and/or

the amino acid residue in P12 is of type C, or of type F; and/or

the amino acid residue in P13 is of type F, or it is Gly or NMeGly; and/or P4 and P11, taken together, form a group of type H; and/or

the amino acid residue in P4 is a D-isomer; and/or

the amino acid residue in P11 is a D-isomer.

If n is 14, the α-amino acid residues in positions 1 to 14 are most preferably:

P1: Tyr, Gln, Arg, His, Ile, Trp, Thr, Glu, Ser, Val, Met, Phe, Gly, Asp, Leu, Pip;

P2: Arg, His, Lys, 4-PyrAla;

P3: Cit; Arg, His, Ile, Tyr, Trp, Pro, Glu, Asn, Asp, Lys, Ala, Leu, Val, 4F-Phe, Met, Ser, Thr, Gln, Tyr;

P4: Val, Phe, Tyr, t-BuG, Cys, Ser, Dab, Glu;

P5: Arg, Dab, Ser, (EA)G;

P6: Pro, Gly, Phe, Val, Cit, Ala;

P7: ^(D)Pro, Pro, Gly, Val;

P8: Arg, Tyr, Trp, Thr, 4F-Phe, Dab, 4-PyrAla, Isorn, (Im)G, Cit, His, IpegDab, ^(D)Pro;

P9: Arg, (Pip)G, (EA)G, Orn, Pro;

P10: 2-Nal, Trp, Tyr;

P11: Phe, Tyr, Val, t-BuG, Cys, Asn, Glu, Dab, Arg;

P12: Tyr, Cit;

P13: Cit, Gln, Arg, His, Tyr, Asn, Asp, Lys, Ala, Ser, Leu, Met, NMeGly, Thr, Cys; and

P14: Lys, Glu, Gln, Asn, Asp, Ala, Ser, NMeK;

with the Proviso that

the amino acid residue in P1 is Pip or Gly; and or

the amino acid residue in P3 is Glu, Asn, Asp, Thr, or Gln; and/or

the amino acid residue in P4 is Cys, Ser, or Glu; and/or

the amino acid residue in P5 is Ser or (EA)G; and/or

the amino acid residue in P6 is Phe, Val, or Ala; and/or

the amino acid residue in P7 is Val, Pro, or ^(D)Pro; and/or

the amino acid residue in P8 is Tyr, Trp, 4F-Phe, 4-PyrAla, (Im)G, His or ^(D)Pro; and/or

the amino acid residue in P9 is (EA)G; and/or

the amino acid in P10 is Val or t-BuG; and/or

the amino acid residue in P12 is Tyr or Cit; and/or

the amino acid residue in P13 is Glu, Gln, Asp, Asn, Ser, Thr, Cys, or NMeGly; and/or

Cys at P4 and P11 form a disulfide bridge; and/or

Glu at P4 and Dab at P11 form a lactam bridge; and/or

Dab at P4 and Glu at P11 form a lactam bridge

If n is 18, the amino acid residues in position 1-18 are most preferably:

P1: of type D, or of type E;

P2: of type E, or of type F;

P3: of type C, or of type D;

P4: of type E, or of type F;

P5: of type D, or of type E;

P6: of type E, or of type F;

P7: of type E, or of type F;

P8: of type E, or of type F, or the residue is Gly or NMeGly;

P9: of type D;

P10: of type E, or of formula -A1-A69-CO—, or the residue is Pro or Pip;

P11: of type E, or of formula —B—CO—, or the residue is Gly, NMeGly, Pro or Pip;

P12: of type D;

P13: of type F, or of type E, or the residue is Gly or NMeGly;

P14: of type C, or of type D;

P15: of type E, or of type F;

P16: of type E or of type F;

P17: of type E, or of type F; and

P18: of Type C or of type D or of type E or of Type F; or

P4 and P17 and/or P6 and P15 and/or P8 and P13, taken together, form a group of type H;

at P10, P11 and P12 also D-isomers being possible.

If n is 18, the α-amino acid residues in positions 1 to 18 are most preferably:

P1: Arg;

P2: Arg;

P3: 2-Nal, Trp, Tyr;

P4: Cys;

P5: Tyr;

P6: Cit, Gln. Arg;

P7: Lys;

P8: Cys, Gly;

P9: Tyr;

P10: Lys, ^(D)Lys, ^(D)Pro;

P11: Gly, Pro, ^(D)Pro;

P12: Tyr;

P13: Cys, Gly;

P14: Tyr;

P15: Arg;

P16: Cit, Thr, Lys;

P17: Cys; and

P18: Arg; or

Cys at P4 and P17 and/or at P8 and

P13 form a disulfide bridge.

Particularly preferred β-peptidomimetics of the invention include those described in Examples 21, 22, 38, 45, 51, 52 53, 55, 56, 60, 61, 68, 75, 84, 85, 87, 101, 102, 105, 110, 120, 132, 147, 151, 152 and 160.

The processes of the invention can advantageously be carried out as parallel array syntheses to yield libraries of template-fixed β-hairpin peptidomimetics of the above general formula I. Such parallel syntheses allow one to obtain arrays of numerous (normally 24 to 192, typically 96) compounds of general formula I in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products. The proper choice of the functionalized solid-support (i.e. solid support plus linker molecule), templates and site of cyclization play thereby key roles.

The functionalized solid support is conveniently derived from polystyrene crosslinked with, preferably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol spacers (Tentagel®); and polyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M, “Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries”, Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. For the purposes of the present invention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acid conditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers of this kind form amides of the carboxyl group of the amino acids; examples of resins functionalized by such linker structures include 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]-4-methylbenzydrylamine PS resin (Rink amide MBHA PS Resin), and 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]benzhydrylamine PS-resin (Rink amide BHA PS resin). Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 4-(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl group under acidic conditions. Linkers of this kind form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin® linker), 4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityl and 2-chlorotrityl. Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotrityl linker.

When carried out as a parallel array syntheses the processes of the invention can be advantageously carried out as described herein below but it will be immediately apparent to those skilled in the art how these procedures will have to be modified in case it is desired to synthesize one single compound of the above formula I.

A number of reaction vessels (normally 24 to 192, typically 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 100 mg, of the appropriate functionalized solid support, preferably 1 to 3% cross-linked polystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE), isopropylalcohol and the like. Solvent mixtures containing as at least one component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of the resin-bound peptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991, 113, 4202-4207).

With the development of various linkers that release the C-terminal carboxylic acid group under mild acidic conditions, not affecting acid-labile groups protecting functional groups in the side chain(s), considerable progresses have been made in the synthesis of protected peptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker (Sasrin® linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during the peptide synthesis, Boc/tBu-based additional protecting groups being compatible with this protection scheme. Other linkers which are suitable for the process of the invention include the super acid labile 4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of the peptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid in DCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker (HMPB-linker, Flörsheimer & Riniker, Peptides 1991, 1990 131) which is also cleaved with 1% TFA/DCM in order to yield a peptide fragment containing all acid labile side-chain protective groups; and, in addition, the 2-chlorotritylchloride linker (Barlos et al., Tetrahedron Lett. 1989, 30, 3943-3946), which allows the peptide detachment using a mixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for their residues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain         of lysine)         Cbz benzyloxycarbonyl         Boc tert.-butyloxycarbonyl         Fmoc 9-fluorenylmethoxycarbonyl         Alloc allyloxycarbonyl         Teoc trimethylsilylethoxycarbonyl         Tcc trichloroethoxycarbonyl         Nps o-nitrophenylsulfonyl;         Trt triphenymethyl or trityl     -   for the carboxyl group (as is present e.g. also in the         side-chain of aspartic and glutamic acid) by conversion into         esters with the alcohol components         tBu tert.-butyl         Bn benzyl         Me methyl         Ph Phenyl         Pac Phenacyl     -   Allyl         Tse trimethylsilylethyl         Tce trichloroethyl;     -   for the guanidino group (as is present e.g. in the side-chain of         arginine)         Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl         Ts tosyl (i.e. p-toluenesulfonyl)         Cbz benzyloxycarbonyl         Pbf Pentamethyldihydrobenzofuran-5-sulfonyl     -   for the hydroxy group (as is present e.g. in the side-chain of         threonine and serine)         tBu tert.-butyl         Bn benzyl         Trt trityl     -   and for the mercapto group (as is present e.g. in the side-chain         of cysteine)         Acm acetamidomethyl         tBu tert.-butyl         Bn benzyl         Trt trityl         Mtr 4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivatives are preferably used as the building blocks for the construction of the template-fixed β-hairpin loop mimetics of formula I. For the deprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.

N-substituted glycine derivatives (type 1) used as building blocks for the construction of certain compounds of formula I are derived from 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivatives or, alternatively, built up in two steps from leaving group-containing glycine precursors, such as bromo, chloro or iodo acetic acid, and suitable primary amine building blocks NH₂—R⁸⁶. The first synthesis step consists of the attachment of the leaving group-containing acetylating agent, such as bromo acetic acid, to the resin bound intermediate through formation of the amide bond. The second reaction step—the nucleophilic displacement—is accomplished using the primary amine building blocks, wherein the residues are, if necessary, suitably protected with groups as described above for side chains of amino acids.

For the incorporation of the N-substituted glycine derivatives as building blocks into the template-fixed β-hairpin loop mimetics the general synthesis procedure for assembling the hairpin mimetics is used as described herein.

The quantity of the reactant, i.e. of the amino acid derivative, is usually 1 to 20 equivalents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time. The reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together. Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like. The gas flow may also be heated or chilled prior to flow through the manifold. Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling externally with isopropanol/dry ice and the like to bring about the desired synthetic reactions. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). The preferred workstations (without, however, being limited thereto) are Labsource's Combi-chem station and MultiSyn Tech's-Syro synthesizer.

Amide bond formation requires the activation of the α-carboxyl group for the acylation step. When this activation is being carried out by means of the commonly used carbodiimides such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res. Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and diisopropylurea is insoluble and, respectively, soluble in the solvents generally used. In a variation of the carbodiimide method 1-hydroxybenzotriazole (HOBt, Kinig & Geiger, Chem. Ber 1970, 103, 788-798) is included as an additive to the coupling mixture. HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions. Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphonium hexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14, 1219-1222; Synthesis, 1976, 751-752), or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophoshate (Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or 2-(1H-benzotriazol-1-yl-) 1,1,3,3-tetramethyluronium terafluoroborate (TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett. 1989, 30, 1927-1930); these phosphonium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives. More recently diphenoxyphosphoryl azide (DPPA) or O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU) or O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpino et al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used as coupling reagents.

Due to the fact that near-quantitative coupling reactions are essential, it is desirable to have experimental evidence for completion of the reactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970, 34, 595), where a positive colorimetric response to an aliquot of resin-bound peptide indicates qualitatively the presence of the primary amine, can easily and quickly be performed after each coupling step. Fmoc chemistry allows the spectrophotometric detection of the Fmoc chromophore when it is released with the base (Meienhofer et al., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure solvent(s) by one of the two following methods:

-   -   1) The reaction wells are filled with solvent (preferably 5 ml),         the reaction tubes, in combination with the holder block and         manifold, are immersed and agitated for 5 to 300 minutes,         preferably 15 minutes, and drained by gravity followed by gas         pressure applied through the manifold inlet (while closing the         outlet) to expel the solvent;     -   2) The manifold is removed from the holder block, aliquots of         solvent (preferably 5 ml) are dispensed through the top of the         reaction tubes and drained by gravity through a filter into a         receiving vessel such as a test tube or vial.

Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times), monitoring the efficiency of reagent, solvent, and by-product removal by methods such as TLC, GC, or inspection of the washings.

The above described procedure of reacting the resin-bound compound with reagents within the reaction wells followed by removal of excess reagents, by-products, and solvents is repeated with each successive transformation until the final resin-bound fully protected linear peptide has been obtained.

Before this fully protected linear peptide is detached from the solid support, it is possible, if desired, to selectively deprotect one or several protected functional group(s) present in the molecule and to appropriately substitute the reactive group(s) thus liberated. To this effect, the functional group(s) in question must initially be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example for such an amino protecting group for which can be selectively removed, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, without affecting the remaining protecting groups, such as Fmoc, present in the molecule. The reactive group thus liberated can then be treated with an agent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated by means of an acylating agent corresponding to the acyl substituent to be introduced. For the formation of the pegylated amino acids such as IPegK, or SPegK, preferably a solution of 5 equivalents of HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalents of DIPEA (Diisopropyl ethaylamine) in dry DMF and 5 equivalents of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (IPeg) and, respectively, 2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated amino group of the appropriate amino acid side chain for 3 h. The procedure is thereafter repeated for another 3 h with a fresh solution of reagents after filtering and washing the resin.

Before this fully protected linear peptide is detached from the solid support, it is also possible, if desired, to form (an) interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the β-strand region.

Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bridges formed by cysteine and homocysteine residues at opposite positions of the β-strand; or lactam bridges formed by glutamic and aspartic acid residues linking ornithine and, respectively, lysine residues, or by glutamic acid residues linking 2,4-diaminobutyric acid residues located at opposite β-strand positions by amide bond formation. The formation of such interstrand linkages can be effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10 equivalents of iodine solution is applied in DMF or in a mixture of CH₂Cl₂/MeOH for 1.5 h which is repeated is repeated for another 3 h with a fresh iodine solution after filtering of the iodine solution, or in a mixture of DMSO and acetic acid solution, buffered with 5% with NaHCO₃ to pH 5-6 for 4 h, or in water after adjusted to pH 8 with ammonium hydroxide solution by stirring for 24 h, or in a solution of NMP and tri-n-butylphosphine (preferably 50 eq.).

For the formation of lactam bridges preferably a solution of 2 equivalents of HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide) in dry DMF and a solution of 4 equivalents of DIPEA (Diisopropyl ethaylamine) in dry DMF is applied for 16 h.

Detachment of the fully protected linear peptide from the solid support is achieved by immersion of the reaction tubes, in combination with the holder block and manifold, in reaction wells containing a solution of the cleavage reagent (preferably 3 to 5 ml). Gas flow, temperature control, agitation, and reaction monitoring are implemented as described above and as desired to effect the detachment reaction. The reaction tubes, in combination with the holder block and manifold, are disassembled from the reservoir block and raised above the solution level but below the upper lip of the reaction wells, and gas pressure is applied through the manifold inlet (while closing the outlet) to efficiently expel the final product solution into the reservoir wells. The resin remaining in the reaction tubes is then washed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent to extract (wash out) as much of the detached product as possible. The product solutions thus obtained are combined, taking care to avoid cross-mixing. The individual solutions/extracts are then manipulated as needed to isolate the final compounds. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivatives which have been cleaved off from the solid support and neutralized with a base, are evaporated. Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents which were mentioned earlier can be used for the cyclization. The duration of the cyclization is about 6-48 hours, preferably about 16 hours. The progress of the reaction is followed, e.g. by RP-HPLC (Reverse Phase High Performance Liquid Chromatography). Then the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.

Alternatively the detachment and complete deprotection of the fully protected peptide from the solid support can be achieved manually in glass vessels.

Finally, the fully protected peptide derivative is treated with 95% TFA, 2.5% H₂O, 2.5% TIS or another combination of scavengers for effecting the cleavage of protecting groups. The cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles are evaporated to dryness and the crude peptide is dissolved in 20% AcOH in water and extracted with isopropyl ether or other solvents which are suitable therefor. The aqueous layer is collected and evaporated to dryness, and the fully deprotected cyclic peptide derivative of formula I is obtained as end-product. Depending on its purity, this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to convert a fully deprotected product of formula I thus obtained into a pharmaceutically acceptable salt or to convert a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt. Any of these operations can be carried out by methods well known in the art.

The template starting materials of formula II used in the processes of the invention, pre-starting materials therefor, and the preparation of these starting and pre-starting materials are described in International Application PCT/EP02/01711 of the same applicants, published as WO 02/070547 A1.

The starting materials of formula H₂NR⁸⁶ are known or can be prepared by methods which are well known in the art.

The β-hairpin peptidomimetics of the invention can be used in a wide range of applications in order to prevent HIV infections in healthy individuals and slow or halt viral progression in infected patients, or where cancer is mediated or resulting from the CXCR4 receptor activity, or where immunological diseases are mediated or resulting from CXCR4 receptor activity, or the β-hairpin peptidomimetics of the invention can be used to treat immuno suppression, or they can be used during apheresis collections of peripheral blood stem cells.

The β-hairpin peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.

When used to treat or prevent HIV infections or cancer such as breast cancer, brain cancer, prostate cancer, lung cancer, kidney cancer, neuroblastoma, non-hodgkin's lymphoma, ovarian cancer, multiple myeloma, chronic lyphomphocytic leukemia, pancreatic cancer, melanoma, angiogenesis, and haematopoetic tissues; or inflammatory disorders such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing sponylitis, systemic sclerosis, Sjogren's syndrome, systemic anaphylaxis or hypersensitivity responses, drug allergies, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, including allograft rejection or graft-versus-host disease, inflammatory bowel diseases, inflammatory dernatoses; or to treat immunosuppression, including immunosuppression induced by chemotherapy, radiation therapy or graft/transplantation rejection, the β-hairpin peptidomimetics can be administered singly, as mixtures of several, β-hairpin peptidomimetics, in combination with other anti-HIV agents, or antimicrobial agents or anti cancer agents or anti-inflammatory agents, or in combination with other pharmaceutically active agents. The β-hairpin peptidomimetics can be administered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active β-hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the β-hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated by combining the active β-hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. Such carriers enable the β-hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.

For administration by inhalation, the, β-hairpin peptidomimetics of the invention are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the β-hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the β-hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the β-hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

As the β-hairpin pepdidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.

For topical administration to treat or prevent HIV infections a therapeutically effective dose can be determined using, for example, the in vitro assays provided in the examples. The treatment may be applied while the HIV infection is visible, or even when it is not visible. An ordinary skilled expert will be able to determine therapeutically effective amounts to treat topical HIV infections without undue experimentation.

For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating β-hairpin peptidomimetic concentration range that includes the IC₅₀ as determined in the cell culture (i.e. the concentration of a test compound that is lethal to 50% of a cell culture). Such information can be used to more accurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

Dosage amounts for applications as anti-HIV agents may be adjusted individually to provide plasma levels of the β-hairpin peptidomimetics of the invention which are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.

In cases of local administration or selective uptake, the effective local concentration of the β-hairpin peptidomimetics of the invention may not be related to plasma concentration. One having the ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician.

The anti-HIV therapy may be repeated intermittently while infections are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs, such as for example other anti-HIV agents or anti cancer agents, or other antimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD₅₀ (the dose lethal to 50% of the population) or the LD₁₀₀ (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the β-hairpin peptidomimetics of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. Fingl et al. 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the invention in more detail but are not intended to limit its scope in any way. The following abbreviations are used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetramethylurounium         hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,         1927-1930);     -   HOBt: 1-hydroxybenzotriazole;     -   DIEA: diisopropylethylamine;     -   HOAT: 7-aza-1-hydroxybenzotriazole;     -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium         hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,         2279-2281).

EXAMPLES 1. Peptide Synthesis

Coupling of the First Protected Amino Acid Residue to the Resin

0.5 g of 2-chlorotritylchloride resin (Barlos et al. Tetrahedron Lett. 1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a dried flask. The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swell at room temperature under constant stirring for 30 min. The resin was treated with 0.415 mMol (1 eq) of the first suitably protected amino acid residue (see below) and 284 μl (4 eq) of diisopropylethylamine (DIEA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours. The resin colour changed to purple and the solution remained yellowish. The resin was shaken (CH₂Cl₂/MeOH/DIEA:17/2/1), 30 ml for 30 min; then washed in the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and dried under vacuum for 6 hours. Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared: Fmoc-ProO-chlorotritylresin, Fmoc-^(D)ProO-chlorotritylresin, and Fmoc-S-(4-S-Alloc-amino)-ProO-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels. In each vessel were placed 60 mg (weight of the resin before loading) of the above resin. The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 3 × 1 min. 2 DMF, wash and swell 1 × 5 min. 3 40% piperidine/DMF 1 × 5 min. 4 DMF, wash 5 × 2 min. 5 5 equiv. Fmoc amino acid/DMF + 1 × 120 min.  5 eq. HBTU + 5 eq. HOBt + 5 eq. DIEA 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at the end of the synthesis) 3 × 2 min.

Steps 3 to 6 are repeated to add each amino-acid.

Pegylation of Side Chain Amino Functions with 2-[2-(2-methoxyethoxy)ethox]acetic acid and 2-(2-methoxyethoxy)acetic acid

The resin (0.040 mmol) containing the peptide was swollen in 5 ml of freshly distilled CH₂Cl₂ for 30 min and then the palladium catalyst Pd(PPh₃)₄, 14 mg, 0.3 eq, was added followed by PhSiH₃, 0.8 mmol, 20 eq. The resin was shaken for 2 h and the reaction solution was filtered off. The reaction was repeated again by employing the same amount of reagents and after 2 h the resin was washed with CH₂Cl₂ and DMF and finally with Et₂O. The resin was swollen again in freshly distilled CH₂Cl₂ (2 ml) for 30 min, the solvent was filtered off and the resin swollen in DMF for 1 h. A solution of DIPEA (10 eq) in 1 ml of DMF was added followed by the addition of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid or 2-(2-methoxyethoxy)acetic acid (5 eq) and finally by a solution of HATU (5 eq) in 1 ml of DMF. The resin was shaken for 3 h and the reaction solution was filtered off. The reaction was repeated again by employing the same amount of reagents and after 3 h the resin was washed with CH₂Cl₂ and DMF and finally with Et₂O.

The pegylation procedure was performed optionally, after the synthesis of the fully protected peptide fragment had been terminated, and then subsequently either Procedure A, Procedure B or Procedure C, as described hereinbelow, was adopted, depending on whether no intertrand linkages or disulfide, β-strand linkages or lactam β-strand linkages were to be formed.

Procedure A: Cyclization and Work Up of Backbone Cyclized Peptides

Cleavage of the Fully Protected Peptide Fragment

After completion of the synthesis, the resin was suspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes, filtered and the filtrate was neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion of the cleavage. The filtrate was evaporated to dryness and the product was fully deprotected [cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS)] to be analyzed by reverse phase-HPLC (column C₁₈) and ESI-MS to monitor the efficiency of the linear peptide synthesis.

Cyclization of the Linear Peptide

100 mg of the fully protected linear peptide were dissolved in DMF (9 ml, conc. 10 mg/ml). Then 41.8 mg (0.110 mMol, 3 eq.) of HATU, 14.9 mg (0.110 mMol, 3 eq) of HOAt and 1 ml (0.584 mMol) of 10% DIEA in DMF (v/v) were added, and the mixture was vortexed at 20° C. for 16 hours and subsequently concentrated under high vacuum. The residue was partitioned between CH₂Cl₂ and H₂O/CH₃CN (90/10: v/v). The CH₂Cl₂ phase was evaporated to yield the fully protected cyclic peptide.

Deprotection and Purification of the Cyclic Peptide

The cyclic peptide obtained was dissolved in 1 ml of the cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS). The mixture was left to stand at 20° C. for 2.5 hours and then concentrated under vacuum. The residue was dissolved in a solution of H₂O/acetic acid (75/25: v/v) and the mixture was extracted with di-isopropylether.

The water phase was dried under vacuum and then the product was purified by preparative reverse phase HPLC.

After lyophilisation the products were obtained as white powders and analysed by ESI-MS. The analytical data comprising purity after preparative HPLC and ESI-MS are shown in Tables 1, 2 and 3.

Analytical Method 1:

Analytical HPLC retention times (RT, in minutes) were determined using a VYDAC 218MS5215 column with the following solvents A (H₂O+0.02% TFA) and B (CH₃CN) and the gradient: 0 min: 92% A, 8% B; 8 min: 62% A 38% B; 9-12 min: 0% A, 100% B.

Analytical Method 2:

Analytical HPLC retention times (RT, in minutes) were determined using an EX (s.n. 217808-2 column with the following solvents A (H₂O+0.02% TFA) and B (CH₃CN) and the gradient: 0 min: 95% A, 5% B; 8 min: 30% A 70% B; 9 min: 0% A, 100% B; 9-12 min: 95% A, 5% B.

Procedure B: Cyclization and Work Up of Backbone Cyclized Peptides Having Disulfide β-Strand Linkages

Formation of Disulfide β-Strand Linkage

After completion of the synthesis, the resin was swelled in 3 ml of dry DMF for 1 h. Then 10 eq. of iodine solution in DMF (6 ml) were added to the reactor, followed by stirring for 1.5 h. The resin was filtered and a fresh solution of iodine (10 eq.) in DMF (6 ml) was added, followed by stirring for another 3 h. The resin was filtered and washed with DMF (3×) and CH₂Cl₂ (3×).

Backbone Cyclization, Cleavage and Purification of the Peptide

After formation of the disulfide β-strand linkage, the resin was suspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes and filtered, and the filtrate was neutralized with 1 (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion of the cleavage.

The volatiles were removed and 6 ml dry DMF were added to the tube. Then 2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1 ml) were added to the peptide, followed by stirring for 16 h. The volatiles were evaporated to dryness. The crude cyclised peptide was dissolved in 7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in H₂O (4.5 ml) three times. The CH₂Cl₂ layer was evaporated to dryness. To deprotect the peptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) were added, and the mixture was kept for 2.5 h. The volatiles were evaporated to dryness and the crude peptide was dissolved in 20% AcOH in water (7 ml) and extracted with isopropyl ether (4 ml) for three times. The aqueous layer was collected and evaporated to dryness, and the residue was purified by preparative reverse phase HPLC.

After lyophilisation the products were obtained as white powders and analysed by ESI-MS analytical method 1 or 2. The analytical data comprising purity after preparative HPLC and ESI-MS are shown in Tables and 1, 2 and 3.

Procedure C: Cyclization and Work Up of Backbone Cyclized Peptides Having Lactam β-Strand Linkages

Formation of Lactam β-Strand Linkage

0.036 mmol of the resin was taken in a reactor and swelled in dry DMF for 1 hr. To this 41.60 mg (1 eq.) of Pd(PPh₃)₄ and 0.133 ml (30 eq.) of PhSiH₃ were added and stirred overnight. The resin was filtered and washed thoroughly with DCM and DMF. The resin was swelled again in dry DMF for 1 hr. To this 1 ml DIPEA solution in DMF (24.64 μL of DIPEA in 1 ml DMF, 4 eq.) was added followed by 1 ml HATU solution in DMF (27.37 mg of HATU, 2 eq.) and the final volume of the reaction mixture was 7 ml and stirred overnight. The resin was washed thoroughly with DMF, CH₂Cl₂, DF, CH₂Cl₂.

Backbone Cyclization, Cleavage and Purification of the Peptide

The peptide was cleaved from the resin by 1% TFA in DCM and evaporated to dryness and 8 ml of dry DMF added to the tube. 2 equivalents of HATU in dry DMF (1 ml) and 4 equivalents of DIPEA in dry DMF (1 ml) were added to the peptide and stirred for 16 h. The volatiles were evaporated to dryness. The crude cyclised peptide was dissolved in 7 ml of DCM and extracted with 10% acetonitrile in H₂O (4.5 ml) three times. The DCM layer was evaporated to dryness.

The crude cyclised peptide was dissolved in 7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in H₂O (4.5 ml) three times. The CH₂Cl₂ layer was evaporated to dryness. To deprotect the peptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) were added, and the mixture was kept for 2.5 h. The volatiles were evaporated to dryness and the crude peptide was dissolved in 20% AcOH in water (7 ml) and extracted with isopropyl ether (4 ml) for three times. The aqueous layer was collected and evaporated to dryness, and the residue was purified by preparative reverse phase HPLC.

After lyophilisation the products were obtained as white powders and analysed by ESI-MS analytical method 1 or 2. The analytical data comprising purity after preparative HPLC and ESI-MS are shown in Tables 1, 2 and 3.

Examples 1-6 and 8-11 (n=12) are shown in Table 1. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to the procedure described above in the following sequence: Resin-Pro-^(D)Pro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter they were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure A.

HPLC-retention times (minutes) were determined using the gradient method 1 as described above:

-   -   Ex. 1 (4.98); Ex. 2 (4.62); Ex. 3 (5.63); Ex. 4 (5.33); Ex. 5         (5.12), Ex. 6 (4.75); Ex. 8 (5.08); Ex. 9 (6.17); Ex. 10 (6.28);         Ex. 11 (6.57).

Examples 7 and 12-14 (n=12) are shown in Table 1, The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P. Thereafter the disulfide bridges were formed and the peptides were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method 1 described above:

-   -   Ex. 7 (4.48); Ex. 12 (4.83); Ex. 13 (5.30); Ex. 14 (4.08).

Examples 15-50 (n=14) are shown in Table 2. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter they were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure A.

HPLC-retention times (minutes) were determined using the gradient method 1 described above:

-   -   Ex. 15 (5.35); Ex. 16 (5.48); Ex. 17 (5.85); Ex. 18 (5.78); Ex.         19 (4.82); Ex. 20 (5.33); Ex. 21 (5.77), Ex. 22 (5.85); Ex. 23         (6.22); Ex. 24 (6.22); Ex. 25 (4.48); Ex. 26 (5.08); Ex. 27         (6.17); Ex. 28 (6.28); Ex. 29 (6.57); Ex. 30 (6.73); Ex. 31         (5.60); Ex. 32 (5.58); Ex. 33 (5.85); Ex. 34 (6.20); Ex. 35         (6.33); Ex. 36 (5.43); Ex. 37 (5.85); Ex. 38 (5.92); Ex. 39         (5.47); Ex. 40 (6.0, 6.37)*; Ex. 41 (5.13); Ex. 42 (5.00); Ex.         43 (5.00); Ex. 44 (5.33, 5.67)*, Ex. 45 (5.03); Ex. 46 (4.75);         Ex. 47 (5.27); Ex. 48 (5.65, 6.08)*; Ex. 49 (5.03); Ex. 50         (5.75). * double peaks which show correct MS.

Examples 51-115, 117-141, 143-148 (n=14) are shown in Table 2. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridges were formed, and the peptides were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method 1 for examples Ex 51-53, 138-139, for examples 54-115, 117-137, 140-141, 143-148 gradient method 2, as described above:

-   -   Ex. 51 (4.68); Ex. 52 (4.67); Ex. 53 (5.05), Ex. 54 (3.16), Ex.         55 (3.41), Ex. 56 (3.07), Ex. 57 (2.95), Ex. 58 (2.99), Ex. 59         (3.18), Ex. 60 (3.16), Ex. 61 (3.27), Ex. 62 (2.91), Ex. 63         (2.88), Ex. 64 (2.88), Ex. 65 (2.98), Ex. 66 (3.17), Ex. 67         (2.93), Ex. 68 (2.91), Ex. 69 (2.90), Ex. 70 (2.88), Ex. 71         (3.08), Ex. 72 (3.00), Ex. 73 (3.14), Ex. 74 (3.02), Ex. 75         (2.99), Ex. 76 (3.56), Ex. 77 (3.14), Ex. 78 (3.18), Ex. 79         (3.02), Ex. 80 (3.18), Ex. 81 (3.13), Ex. 82 (3.38), Ex. 83         (3.27), Ex. 84 (3.32), Ex. 85 (3.37), Ex. 86 (3.57), Ex. 87         (3.35), Ex. 88 (3.08), Ex. 89 (3.10), Ex. 90 (3.14), Ex. 91         (3.18), Ex. 92 (3.17), Ex. 93 (3.25), Ex. 94 (3.10), Ex. 95         (3.18), Ex. 96 (3.15), Ex. 97 (3.31), Ex. 98 (3.26), Ex. 99         (3.32), Ex. 100 (3.28), Ex. 101 (3.83), Ex. 102 (3.00), Ex. 103         (3.29), Ex. 104 (2.98), Ex. 105 (2.77), Ex. 106 (2.74), Ex. 107         (3.000, Ex. 108 (2.81), Ex. 109 (2.69, 2.75), Ex. 110 (2.76,         2.82*), Ex. 111 (2.73, 2.78), Ex. 112 (2.71), Ex. 113 (2.51),         Ex. 114 (2.97), Ex. 115 (2.95), Ex. 117 (2.70), Ex. 118 (2.78),         Ex. 119 (2.83), Ex. 120 (2.80), Ex. 121 (3.09), Ex. 122 (3.45),         Ex. 123 (2.82), Ex. 124 (3.29), Ex. 125 (3.27), Ex. 126 (3.19),         Ex. 127 (3.05), Ex. 128 (3.86), Ex. 129 (4.76), Ex. 130 (4.43),         Ex. 131 (4.57), Ex. 132 (4.45), Ex. 133 (4.39), Ex. 134 (4.27),         Ex. 135 (4.33), Ex. 136 (2.75), Ex. 137 (2.72), Ex. 138 (4.75),         Ex. 139 (4.25), Ex. 140 (4.77), Ex. 141 (3.27), Ex. 143 (3.01),         Ex. 144 (3.24), Ex. 145 (2.84), Ex. 146 (2.80), Ex. 147 (2.91),         Ex. 148 (2.76). *double peaks which show correct MS.

Example 116 (n=14) is shown in Table 2. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-S-(4S-Alloc-amino)-ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-S-(4-S-Alloc-amino)Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Then the pegylation procedure was applied using 2-[2-(2-methoxyethoxy)ethoxy]acetic acid resulting in ^(D)ProA8″-42 as the template. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 116 (3.00).

Example 142 (n=14) is shown in Table 2. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1. Then the pegylation procedure was applied using 2-[2-(2-methoxyethoxy)ethoxy]acetic acid. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 142 (3.18).

Example 149 (n=14) is shown in Table 2. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Gln-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 149 (2.76).

Example 150 (n=14) is shown in table 2. The peptide was synthesized starting with the amino acid ^(D)Pro which was grafted to the resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-^(D)Pro-Gly-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridge was formed, and the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 150 (2.61).

Example 151 (n=14) is shown in Table 2. The peptide was synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P3-P2-P1. Thereafter the peptide was cleaved from the resin, cyclized, deprotected and purified as indicated in procedure A.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 151 (2.86).

Examples 152-153 (n=14) are shown in Table 2. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-^(D)-Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the lactam bridges were formed, and the peptides were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure C.

HPLC-retention times (minutes) were determined using the gradient method 2 as described above:

-   -   Ex. 152 (2.87), Ex. 153 (2.87, 2.88*). *double peaks which show         correct MS.

Examples 154-155 (n=18) are shown in Table 3. The peptides were synthesized starting with the amino acid ^(D)Pro which was grafted to the resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridges were formed using the following procedure:

For the formation of the disulfide bridge at position P4 and P17 the protected cyclic peptide (36 μmol) was swelled in dry DMF for 1 h. The DMF was drained off and was replaced by 2 ml NMP and 444 μl tri-n-butylphosphine (50 eq.) under argon. The resin was shaken for 2 h.

The solvents were removed and the resin was washed once with 5 ml NMP. Thereafter the resin was shaken again with 2 ml NMP and 444 μl tri-n-butylphosphine (50 eq.) under argon for 2 h. The resin was washed with DMF and transferred with 90 ml DMF into a 250 ml flask. 1 mmol (330 mg) [K₃Fe(CN)₆] in 10 ml water was added and the suspension was agitated gently overnight at 25° C. in the dark. The resin was transferred into a reactor and was washed with once with 7 ml water and twice with 5 ml DMF.

For the formation of the second disulfide bridge at position P8 and P13 the peptide was treated with 9 eq. (83 mg) iodine in 6 ml dry DMF for 2 h. The resin was washed once with DMF and the treatment with 9 eq. (83 mg) iodine in 6 ml DMF was repeated. The resin was washed three times with 5 ml DMF followed by three times with 5 ml CH₂Cl₂. The peptide was then cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method 2 as described above: Ex. 154 (3.18), Ex. 155 (3.06).

Purity: %-purity of compounds after prep. HPLC: Ex. 154 (97), Ex. 155 (95).

Mass: [M+3H]/3: Ex. 154 (785.4), Ex. 155 (875.4).

Examples 156-157 (n=18) are shown in Table 3. The peptides were synthesized starting with the amino acid ^(D)Pro which was grafted to the resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridges were formed, and the peptides were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method 2 as described above: Ex. 156 (3.00), Ex. 157 (2.98).

Purity: %-purity of compounds after prep. HPLC: Ex. 156 (95), Ex. 157 (76)

Mass: [M+3H]/3: Ex. 156 (845.5), Ex. 157(848.8)

Examples 158-159 (n=18) are shown in Table 3. The peptides were synthesized starting with the amino acid Pro which was grafted to the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which was prepared as described above. The linear peptides were synthesized on solid support according to procedure described above in the following sequence: Resin-Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the disulfide bridges were formed, and the peptides were cleaved from the resin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention times (minutes) were determined using the gradient method 2 as described above: Ex. 158 (3.41), Ex. 159 (3.25)

Purity: %-purity of compounds after prep. HPLC: Ex. 158 (95), Ex. 159 (83)

Mass: [M+3H]/3: Ex. 158 (848.8), Ex. 159 (822.1).

Examples 160 (n=18) is shown in Table 3. The peptide was synthesized starting with the amino acid ^(D)Pro which was grafted to the resin. Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was prepared as described above. The linear peptide was synthesized on solid support according to procedure described above in the following sequence: Resin-^(D)Pro-Gly-P18-P17-P16-P15-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter the following procedure was used:

The peptide (36 μmol) was cleaved from the resin by 1% TFA in CH₂Cl₂ After evaporation to dryness 8 ml of dry DMF were added to the tube. Then 2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1 ml) were added and stirring was effected for 16 h. The volatiles were evaporated to dryness. The crude cyclised peptide was dissolved in 7 ml of DCM and extracted with 10% acetonitrile in H₂O (4.5 ml) three times. The organic layer was evaporated to dryness. To deprotect the peptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5) was added and kept for 3 h. The volatiles were evaporated to dryness and the crude peptide was dissolved in 20% acetic acid in water (7 ml) and extracted with isopropyl ether (4 ml) for three times. The aqueous layer was diluted up to 200 ml with water. The pH was adjusted to pH 8 with ammonium hydroxide solution. The reaction mixture was shaken for 24 h. The solution was acidified with acetic acid to pH 5, evaporated to dryness, and purified by HPLC.

HPLC-retention time (minutes) was determined using the gradient method 2 as described above: Ex. 160 (2.92)

Purity: %-purity of compounds after prep. HPLC: Ex. 160 (93)

Mass: [M+3H]/3: Ex. 160 (785.3).

TABLE 1 Examples n = 12 Exam- ple Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Template Purity %^(a)) [M + 2H]/2 1 SEQ ID Tyr Arg Cit Val Arg ^(D)Arg Arg 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 83 1016.1 NO: 1 2 SEQ ID Tyr Arg Cit Val Arg ^(D)Arg Arg 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 992.4 NO: 2 3 SEQ ID Tyr Arg Cit Phe Arg Arg Arg 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 78 1040.4 NO: 3 4 SEQ ID Tyr Arg Cit Val Arg Arg Arg 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 83 1016.7 NO: 4 5 SEQ ID Tyr Arg Cit Phe Arg Arg Arg 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 69 1016.2 NO: 5 6 SEQ ID Tyr Arg Cit Val Arg Arg Arg 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 992.3 NO: 6 7 SEQ ID Tyr Arg Cit Cys Arg Arg Arg 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 92 994.8 NO: 7 8 SEQ ID Tyr Arg Cit Gly Arg Arg Arg 2-Nal Gly Tyr Cit Lys ^(D)Pro^(L)Pro 100 1119.3 NO: 8 8 SEQ ID Tyr Arg Cit Ile Arg Arg Arg 2-Nal Ile Tyr Cit Lys ^(D)Pro^(L)Pro 100 4.98 NO: 9 10 SEQ ID Tyr Arg Cit Thr Arg Arg Arg 2-Nal Thr Tyr Cit Lys ^(D)Pro^(L)Pro 100 993.8 NO: 10 11 SEQ ID Tyr Arg Cit Gln Arg Arg Arg 2-Nal Gln Tyr Cit Lys ^(D)Pro^(L)Pro 100 1162.0 NO: 11 12 SEQ ID Tyr Arg Cit Cys Arg ^(D)Arg Arg 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 996.1 NO: 12 13 SEQ ID Tyr Gly Cit Cys Arg Arg Arg 2-Nal Cys Tyr Gly Lys ^(D)Pro^(L)Pro 64 895.2 NO: 13 14 SEQ ID Tyr Arg Cit Cys Arg Arg Arg Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 87 989.6 NO: 14 ^(a))%-purity of compounds after prep. HPLC Cys in pos. 4 and 9 in Ex. 7, 12-14 form a disulfide bridge

TABLE 2 Examples n = 14 Example Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 15 SEQ ID NO: 15 Tyr Arg Cit Val Arg Val ^(D)Pro Arg Arg 16 SEQ ID NO: 16 Tyr Arg Cit Val Arg Val Pro Arg Arg 17 SEQ ID NO 17 Tyr Arg Cit Val Arg Phe ^(D)Pro Arg Arg 18 SEQ ID NO 18 Tyr Arg Cit Val Arg Phe Pro Arg Arg 19 SEQ ID NO: 19 Tyr Arg Cit Phe Arg Cit ^(D)Pro Arg Arg 20 SEQ ID NO: 20 Tyr Arg Cit Phe Arg Cit Pro Arg Arg 21 SEQ ID NO: 21 Tyr Arg Cit Phe Arg Val ^(D)Pro Arg Arg 22 SEQ ID NO: 22 Tyr Arg Cit Phe Arg Val Pro Arg Arg 23 SEQ ID NO: 23 Tyr Arg Cit Phe Arg Phe ^(D)Pro Arg Arg 24 SEQ ID NO: 24 Tyr Arg Cit Phe Arg Phe Pro Arg Arg 25 SEQ ID NO: 25 Tyr Arg Cit Val Arg Cit ^(D)Pro Arg Arg 26 SEQ ID NO: 26 Tyr Arg Cit Val Arg Cit Pro Arg Arg 27 SEQ ID NO: 27 Tyr Arg Cit Phe Arg Val ^(D)Pro Arg Arg 28 SEQ ID NO: 28 Tyr Arg Cit Phe Arg Val Pro Arg Arg 29 SEQ ID NO: 29 Tyr Arg Cit Phe Arg Phe ^(D)Pro Arg Arg 30 SEQ ID NO: 30 Tyr Arg Cit Phe Arg Phe Pro Arg Arg 31 SEQ ID NO: 31 Tyr Arg Cit Val Arg Cit Pro Arg Arg 32 SEQ ID NO: 32 Tyr Arg Cit Val Arg Val ^(D)Pro Arg Arg 33 SEQ ID NO: 33 Tyr Arg Cit Val Arg Val Pro Arg Arg 34 SEQ ID NO: 34 Tyr Arg Cit Val Arg Phe ^(D)Pro Arg Arg 35 SEQ ID NO: 35 Tyr Arg Cit Val Arg Phe Pro Arg Arg 36 SEQ ID NO: 36 Tyr Arg Cit Phe Arg Cit ^(D)Pro Arg Arg 37 SEQ ID NO: 37 Tyr Arg Cit Phe Arg Cit Pro Arg Arg 38 SEQ ID NO: 38 Tyr Arg Cit Phe Arg Gly ^(D)Pro Arg Arg 39 SEQ ID NO: 39 Tyr Arg Cit Phe Arg Gly Gly Arg Arg 40 SEQ ID NO: 40 Tyr Arg Cit Phe Arg Val Gly Arg Arg 41 SEQ ID NO: 41 Tyr Arg Cit Tyr Arg Pro Val Arg Arg 42 SEQ ID NO: 42 Tyr Arg Cit Tyr Arg Pro Val Arg Arg 43 SEQ ID NO: 43 Tyr Arg Cit Tyr Arg Val Gly Arg Arg 44 SEQ ID NO: 44 Tyr Arg Cit Val Arg Pro Val Arg Arg 45 SEQ ID NO: 45 Tyr Arg Cit Val Arg Gly ^(D)Pro Arg Arg 46 SEQ ID NO: 46 Tyr Arg Cit Val Arg Gly Gly Arg Arg 47 SEQ ID NO: 47 Tyr Arg Cit Val Arg Val Gly Arg Arg 48 SEQ ID NO: 48 Tyr Arg Cit t-BuG Arg Pro Val Arg Arg 49 SEQ ID NO: 49 Tyr Arg Cit t-BuG Arg Gly Gly Arg Arg 50 SEQ ID NO: 50 Tyr Arg Cit t-BuG Arg Val Gly Arg Arg 51 SEQ ID NO: 51 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 52 SEQ ID NO: 52 Tyr Arg Cit Cys Arg Gly Gly Arg Arg 53 SEQ ID NO: 53 Tyr Arg Cit Cys Arg Val Gly Arg Arg 54 SEQ ID NO 54 Tyr Arg Cit Cys Arg Gly ^(D)Pro Tyr Arg 55 SEQ ID NO 55 Tyr Arg Cit Cys Arg Gly ^(D)Pro Trp Arg 56 SEQ ID NO 56 Tyr Arg Cit Cys Arg Gly ^(D)Pro Thr Arg 57 SEQ. ID NO 57 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 58 SEQ. ID NO 58 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 59 SEQ. ID NO 59 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 60 SEQ. ID NO 60 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 61 SEQ. ID NO 61 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 62 SEQ. ID NO 62 Gln Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 63 SEQ. ID NO 63 Arg Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 64 SEQ. ID NO 64 His Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 65 SEQ. ID NO 65 Ile Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 66 SEQ. ID NO 66 Trp Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 67 SEQ. ID NO 67 Thr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 68 SEQ. ID NO 68 Glu Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 69 SEQ. ID NO 69 Tyr Arg Arg Cys Arg Gly ^(D)Pro Arg Arg 70 SEQ. ID NO 70 Tyr Arg His Cys Arg Gly ^(D)Pro Arg Arg 71 SEQ. ID NO 71 Tyr Arg Ile Cys Arg Gly ^(D)Pro Arg Arg 72 SEQ. ID NO 72 Tyr Arg Tyr Cys Arg Gly ^(D)Pro Arg Arg 73 SEQ. ID NO 73 Tyr Arg Trp Cys Arg Gly ^(D)Pro Arg Arg 74 SEQ. ID NO 74 Tyr Arg Pro Cys Arg Gly ^(D)Pro Arg Arg 75 SEQ. ID NO 75 Tyr Arg Glu Cys Arg Gly ^(D)Pro Arg Arg 76 SEQ. ID NO 76 Tyr Arg Cit Cys Arg Gly ^(D)Pro 4F-Phe Arg 77 SEQ. ID NO 77 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 78 SEQ. ID NO 78 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 79 SEQ. ID NO 79 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 80 SEQ. ID NO 80 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 81 SEQ. ID NO 81 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 82 SEQ. ID NO 82 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 83 SEQ. ID NO 83 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 84 SEQ. ID NO 84 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 85 SEQ. ID NO 85 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 86 SEQ. ID NO 86 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 87 SEQ. ID NO 87 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 88 SEQ. ID NO 88 Asp Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 89 SEQ. ID NO 89 Ser Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 90 SEQ. ID NO 90 Val Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 91 SEQ. ID NO 91 Met Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 92 SEQ. ID NO 92 Tyr Arg Asn Cys Arg Gly ^(D)Pro Arg Arg 93 SEQ. ID NO 93 Tyr Arg Asp Cys Arg Gly ^(D)Pro Arg Arg 94 SEQ. ID NO 94 Tyr Arg Lys Cys Arg Gly ^(D)Pro Arg Arg 95 SEQ. ID NO 95 Tyr Arg Ala Cys Arg Gly ^(D)Pro Arg Arg 96 SEQ. ID NO 96 Tyr Arg Ser Cys Arg Gly ^(D)Pro Arg Arg 97 SEQ. ID NO 97 Tyr Arg Leu Cys Arg Gly ^(D)Pro Arg Arg 98 SEQ. ID NO 98 Tyr Arg Val Cys Arg Gly ^(D)Pro Arg Arg 99 SEQ. ID NO 99 Tyr Arg 4F-Phe Cys Arg Gly ^(D)Pro Arg Arg 100 SEQ. ID NO 100 Tyr Arg Met Cys Arg Gly ^(D)Pro Arg Arg 101 SEQ. ID NO 101 Tyr Arg Cit Cys Ser Gly ^(D)Pro Arg Arg 102 SEQ. ID NO 102 Tyr Arg Ser Cys Arg Gly ^(D)Pro Arg Arg 103 SEQ. ID NO 103 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 104 SEQ. ID NO 104 Tyr Arg Thr Cys Arg Gly ^(D)Pro Dab Arg 105 SEQ. ID NO 105 Tyr His Cit Cys Arg Gly ^(D)Pro Arg Arg 106 SEQ. ID NO 106 Tyr Lys Cit Cys Arg Gly ^(D)Pro Arg Arg 107 SEQ. ID NO 107 Phe Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 108 SEQ. ID NO 108 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 109 SEQ. ID NO 109 Tyr Arg Cit Cys Arg Gly ^(D)Pro Dab Arg 110 SEQ. ID NO 110 Tyr Arg Thr Cys Arg Gly ^(D)Pro Dab Arg 111 SEQ. ID NO 111 Tyr Arg Cit Cys Dab Gly ^(D)Pro Arg Arg 112 SEQ. ID NO 112 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 113 SEQ. ID NO 113 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 114 SEQ. ID NO 114 Gly Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 115 SEQ. ID NO 115 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 116 SEQ. ID NO 116 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 117 SEQ. ID NO 117 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Orn 118 SEQ. ID NO 118 Tyr Arg Thr Cys Arg Gly ^(D)Pro 4-Pyr AlaArg 119 SEQ. ID NO 119 Tyr 4-PyrAla Thr Cys Arg Gly ^(D)Pro Arg Arg 120 SEQ. ID NO 120 Tyr His Thr Cys Arg Gly ^(D)Pro Arg His 121 SEQ. ID NO 121 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 122 SEQ. ID NO 122 Tyr Arg Cit Cys Arg Gly ^(D)Pro 4F-Phe Arg 123 SEQ. ID NO 123 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 124 SEQ. ID NO 124 Tyr Arg Cit Cys Arg Gly ^(D)Pro IsOrn Arg 125 SEQ. ID NO 125 Tyr Arg Cit Cys Arg Gly ^(D)Pro (Im)G Arg 126 SEQ. ID NO 126 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg (Pip)G 127 SEQ. ID NO 127 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 128 SEQ. ID NO 128 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 129 SEQ. ID NO 129 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 130 SEQ. ID NO 130 Tyr Arg Gln Cys Arg Gly ^(D)Pro Arg Arg 131 SEQ. ID NO 131 Tyr Arg Thr Cys Arg Gly ^(D)Pro Arg Arg 132 SEQ. ID NO 132 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 133 SEQ. ID NO 133 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 134 SEQ. ID NO 134 Tyr Arg Cit Cys Arg Gly ^(D)Pro Dab Arg 135 SEQ. ID NO 135 Tyr Arg Cit Cys Arg Gly ^(D)Pro Dab Arg 136 SEQ. ID NO 136 Tyr Arg Cit Cys Arg Gly ^(D)Pro Cit Arg 137 SEQ. ID NO 137 Tyr Arg Cit Cys Arg Gly ^(D)Pro His Arg 138 SEQ. ID NO 138 Tyr Arg Cit Cys (EA)G Gly ^(D)Pro Arg Arg 139 SEQ. ID NO 139 Tyr Arg Cit Cys Arg Gly Pro Arg (EA)G 140 SEQ. ID NO 140 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 141 SEQ. ID NO 141 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 142 SEQ. ID NO 142 Tyr Arg Cit Cys Arg Gly ^(D)Pro IPegDab Arg 143 SEQ. ID NO 143 Tyr Arg Cit Cys Arg Ala ^(D)Pro Arg Arg 144 SEQ. ID NO 144 Leu Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 145 SEQ. ID NO 145 Tyr Arg Thr Cys Arg Gly ^(D)Pro Arg Arg 146 SEQ. ID NO 146 Tyr Arg Thr Cys Arg Gly ^(D)Pro Arg Arg 147 SEQ. ID NO 147 Tyr Arg Ile Cys Arg Gly ^(D)Pro Arg Arg 148 SEQ. ID NO 148 Tyr Arg Tyr Cys Arg Gly ^(D)Pro Arg Arg 149 SEQ. ID NO 149 Tyr Arg Cit Cys Arg Gly ^(D)Pro Arg Arg 150 SEQ. ID NO 150 Pip Arg Tyr Cys Tyr Gln Lys ^(D)Pro Pro 151 SEQ. ID NO 151 Tyr Arg Cit Ser Arg Gly ^(D)Pro Arg Arg 152 SEQ. ID NO 152 Tyr Arg Cit Dab Arg Gly ^(D)Pro Arg Arg 153 SEQ. ID NO 153 Tyr Arg Cit Glu Arg Gly ^(D)Pro Arg Arg Example P10 P11 P12 P13 P14 Template Purity %^(a)) [M + 2H]/2 15 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1090.2 16 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1090.4 17 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.8 18 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.9 19 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1143.6 20 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1143.3 21 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 99 1114.3 22 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.3 23 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.1 24 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.3 25 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1119.3 26 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1119.3 27 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.7 28 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.3 29 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1162.3 30 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1219.3 31 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1143.3 32 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.2 33 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1114.3 34 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.9 35 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1138.3 36 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1167.6 37 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1168.2 38 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1116.8 39 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 100 1096.7 40 2-Nal Phe Tyr Cit Lys ^(D)Pro^(L)Pro 92 1117.6 41 2-Nal Tyr Tyr Cit Lys ^(D)Pro^(L)Pro 96 1153.8 42 2-Nal Tyr Tyr Cit Lys ^(D)Pro^(L)Pro 100 1133.3 43 2-Nal Tyr Tyr Cit Lys ^(D)Pro^(L)Pro 99 1134.0 44 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 93 1089.7 45 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1068.5 46 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 95 1048.8 47 2-Nal Val Tyr Cit Lys ^(D)Pro^(L)Pro 100 1070.3 48 2-Nal t-BuG Tyr Cit Lys ^(D)Pro^(L)Pro 98 1103.6 49 2-Nal t-BuG Tyr Cit Lys ^(D)Pro^(L)Pro 93 1062.4 50 2-Nal t-BuG Tyr Cit Lys ^(D)Pro^(L)Pro 93 1084.3 51 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 1071.7 52 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 1051.6 53 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 100 1073.2 54 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1061.4 55 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1072.9 56 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1030.3 57 2-Nal Cys Tyr Arg Lys ^(D)Pro^(L)Pro 95 1071.8 58 2-Nal Cys Tyr His Lys ^(D)Pro^(L)Pro 95 1061.9 59 2-Nal Cys Tyr Tyr Lys ^(D)Pro^(L)Pro 95 1075.3 60 2-Nal Cys Tyr Gln Gln ^(D)Pro^(L)Pro 95 1057.8 61 2-Nal Cys Tyr Gln Glu ^(D)Pro^(L)Pro 95 1058.3 62 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1040.3 63 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1054.1 64 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1044.8 65 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1032.9 66 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1069.2 67 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1026.7 68 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1040.8 69 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1057.3 70 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1047.5 71 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1035.9 72 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1060.9 73 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1072.3 74 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1027.9 75 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1043.7 76 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1052.9 77 2-Nal Cys Tyr Asn Lys ^(D)Pro^(L)Pro 95 1051.1 78 2-Nal Cys Tyr Asp Lys ^(D)Pro^(L)Pro 95 1051.4 79 2-Nal Cys Tyr Lys Lys ^(D)Pro^(L)Pro 95 1057.8 80 2-Nal Cys Tyr Ala Lys ^(D)Pro^(L)Pro 95 1029.4 81 2-Nal Cys Tyr Ser Lys ^(D)Pro^(L)Pro 95 1037.1 82 2-Nal Cys Tyr Leu Lys ^(D)Pro^(L)Pro 95 1050.5 83 2-Nal Cys Tyr Met Lys ^(D)Pro^(L)Pro 95 1058.9 84 2-Nal Cys Tyr Gln Asn ^(D)Pro^(L)Pro 95 1051.0 85 2-Nal Cys Tyr Gln Asp ^(D)Pro^(L)Pro 95 1051.4 86 2-Nal Cys Tyr Gln Ala ^(D)Pro^(L)Pro 95 1028.9 87 2-Nal Cys Tyr Gln Ser ^(D)Pro^(L)Pro 95 1037.3 88 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1034.1 89 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1019.8 90 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1025.8 91 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1041.3 92 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1036.2 93 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1036.8 94 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1043.3 95 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1014.8 96 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1022.8 97 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1035.9 98 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1028.9 99 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1052.9 100 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1044.9 101 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1023.3 102 Trp Cys Tyr Cit Asp ^(D)Pro^(L)Pro 95 1025.3 103 2-Nal Cys Tyr Cit Glu ^(D)Pro^(L)Pro 95 1072.7 104 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1001.1 105 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1056.4 106 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1051.5 107 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1057.5 108 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1051.0 109 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1023.0 110 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 995.0 111 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1016.9 112 Tyr Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1046.0 113 Tyr Cys Cit Tyr Lys ^(D)Pro^(L)Pro 83 1054.0 114 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1018.0 115 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1057.8 116 Trp Cys Tyr Cit Lys ^(D)ProA8″-42 68 1153.1 117 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 90 1044.5 118 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1019.0 119 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 90 1019.0 120 Trp Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1013.5 121 Trp Cys Tyr Cit Gln ^(D)Pro^(L)Pro 95 1065.5 122 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1070.0 123 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1065.5 124 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1106.1 125 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1075.5 126 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1091.6 127 2-Nal Cys Tyr Cit NMeK ^(D)Pro^(L)Pro 85 1078.1 128 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 93 1066.6 129 2-Nal Cys Tyr NMeGly Lys ^(D)Pro^(L)Pro 89 1029.1 130 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 79 1057.5 131 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 98 1043.9 132 2-Nal Cys Tyr Thr Lys ^(D)Pro^(L)Pro 89 1057.4 133 2-Nal Cys Tyr Thr Lys ^(D)Pro^(L)Pro 90 1044.0 134 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 88 1044.0 135 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1037.0 136 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1066.0 137 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1056.0 138 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 76 1043.9 139 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 90 1044.0 140 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 88 1043.9 141 2-Nal Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1077.1 142 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1117.6 143 Trp Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1072.5 144 2-Nal Cys Tyr Gln Lys ^(D)Pro^(L)Pro 87 1032.9 145 Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 1012.6 146 Tyr Cys Tyr Cit Lys ^(D)Pro^(L)Pro 95 1026.6 147 Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 92 1043.8 148 Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 91 1043.8 149 Tyr Cys Tyr Gln Lys ^(D)Gln^(L)Pro 91 1025.7 150 Tyr Arg Cit Cys Arg Gly^(D)Pro 95 704.2 151 Trp Asn Tyr Cit Lys ^(D)Pro^(L)Pro 67 1065.0 152 Trp Glu Tyr Cit Lys ^(D)Pro^(L)Pro 92 1070.3 153 Trp Dab Tyr Cit Lys ^(D)Pro^(L)Pro 72 1070.4 Cys in pos. 4 and 11 in Ex. 51-149 form a disulfide bridge, Cys in pos. 4 and 13 in Ex. 150 forms a disulfide bridge, Dab resp. Glu in pos. 4 and Glu resp Dab in position 11 in Ex. 152 resp. 153 form a lactame bridge, ^(a))%-purity of compounds after prep. HPLC

TABLE 3 Examples n = 18 Ex. Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 154 SEQ. ID NO 154 Arg Arg 2-Nal Cys Tyr Cit Lys Cys Tyr 155 SEQ. ID NO 155 Arg Arg Trp Cys Tyr Gln Lys Cys Tyr 156 SEQ. ID NO 156 Arg Arg Trp Cys Tyr Gln Lys Gly Tyr 157 SEQ. ID NO 157 Arg Arg Trp Cys Tyr Gln Lys Gly Tyr 158 SEQ. ID NO 158 Arg Arg Trp Cys Tyr Gln Lys Gly Tyr 159 SEQ. ID NO 159 Arg Arg Tyr Cys Tyr Gln Lys Gly Tyr 160 SEQ. ID NO 160 Arg Arg Trp Cys Tyr Arg Lys Cys Tyr Ex. P10 P11 P12 P13 P14 P15 P16 P17 P18 Template 154 Lys Gly Tyr Cys Tyr Arg Cit Cys Arg Gly^(D)Pro 155 Lys Gly Tyr Cys Tyr Arg Cit Cys Arg Gly^(D)Pro 156 Lys Gly Tyr Gly Tyr Arg Cit Cys Arg Gly^(D)Pro 157 ^(D)Lys Gly Tyr Gly Tyr Arg Cit Cys Arg Gly^(D)Pro 158 ^(D)Pro Pro Tyr Gly Tyr Arg Cit Cys Arg Gly^(L)Pro 159 ^(D)Pro Pro Tyr Gly Tyr Arg Thr Cys Arg Gly^(L)Pro 160 Lys Gly Tyr Cys Tyr Arg Lys Cys Arg Gly^(D)Pro Cys in pos. 4 and 17 and pos. 8 and 13 in Ex. 154-155 and 160 form a disulfide bridge, Cys in pos. 4 and 17 in Ex. 156-159 form a disulfide bridge

2. Biological Methods

2.1. Preparation of the Peptides.

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mM unless stated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Ca²⁺⁻ Assay: CXCR4-Antagonizing Activity of the Peptides.

Method 1: 3-4Mio CXCR4 transfected pre-B cells [see references 1, 2 and 3, below] per measurement were resuspended in 200 μl MSB (20 mM 4-(2-Hydroxyethyl)-piperazin-1-ethanesulfonic acid (HEPES), 136 mM NaCl, 4.8 mM KCl and 1 mM CaCl₂) containing 5 mM D-Glucose and were loaded with 0.75 μl of 1 mM Fura-2-acetoxymethylester (Fura-2-AM) for 17 minutes at 37° C. The cells were washed free from Fura-2-AM with a platelet centrifuge and resuspended in 800 μl MSB containing 5 mM D-Glucose. The peptides to be administered were diluted to a 100 fold end concentration in MSB/0.2% PPL, and 8 pd were injected. [Ca²⁺]_(i)-dependent fluorescence change in response to single or sequential stimulation with the peptide was recorded with a fluorimeter at an excitation wavelength of 340 nM and an end emission wavelength of 510 nM [see ref. 4, below]. Measurements were done under continuous stirring at 37° C. The signal intension was calibrated with 3 mM CaCl₂/1 mM lonomycin (maximal fura-2-acetoxymethyester saturation) and 10 μM MnCl₂ (minimal Fura-2-acetoxymethylester saturation) and [Ca²⁺]_(i)-changes are presented in % fura-2-acetoxymethylester saturation. The rate of [Ca²⁺]_(i)-changes was calculated on the basis of the initial [Ca²⁺]_(i)-changes and plotted in dependence of chemokine concentration to obtain a sigmoidal curve and to determine the IC₅₀ values.

MSB: 20 mM HEPES, 136 mM NaCl, 4.8 mM KCl, 1 mM CaCl₂.2H₂O, pH 7.4;

Osmolarity: 310 mOsm adjusted with NaOH or HCl, adjusted with H₂O or PBS.

MSB plus; 5 mM D-glucose in MSB (50 mg/50 mL).

Fura 2-acetoxymethylester: 1 mM stock solution in dimethulsulfoxide.

Method 2: Increases in intracellular calcium were monitored using a Flexstation 384 (Molecular Devices, Sunnyvale Calif.) to assay the peptides for CXCR4 antagonism in a mouse pre-B cell line 300-19 stably transfected with human CXCR4 [see references 1, 2 and 3, below]. The cells were batch loaded with the Calcium 3 Assay kit (Molecular Devices) in assay buffer (Hanks Balanced salt solution, HBSS, 20 mM HEPES, pH 7.4, 0.1% BSA) for 1 h at room temperature and then 200,000 labeled cells were dispensed into black 96 well assays plates (Costar No. 3603). A 20-fold concentrated solution of peptide in assay buffer was added to the cells and the whole plate was centrifuged to settle the cells to the bottom of the wells. Calcium mobilization induced by 10 nM stromal-derived factor-1 (SDF-1) was measured in the Flexstation 384 (excitation, 485 nM; emission, 525 nM) for 90 seconds. A maximal change in fluorescence response above baseline was used to calculate antagonist activity. The data for dose response curves (antagonist concentration versus % maximum response) were fitted to a four parameter logistic equation using SoftmaxPro 4.6 (Molecular Devices), from which IC₅, values were calculated.

2.3. FIGS-Assay™

The assay was performed according to ref. 5, below. Stock dilutions of the peptides (10 mM) were prepared by dissolving in 10 mM Tris-HCl at room temperature. Stock solutions were kept at +4° C., light protected. Working dilution were prepared extemporaneously by serial dilution in Phosphate Buffered Saline (PBS) and added in a final volume of 10 μl directly to the cell cultures. After 48 hours of co-cultivation the cultures were rinsed with PBS and then exposed to glutaraldehyde/formaldehyde (0.2%/2%) in PBS for five minutes. For photometric quantification the fixed cultures were subsequently incubated with ortho-nitro-phenyl-galactopyranoside (ONPG) as a β-galactosidase substrate, which was enzymatically converted into the chromophore ortho-nitrophenol (ONP). The read out is directly obtained by measuring optical density of wells at 405 nm in an iEMS 96 well-plate reader.

2.4. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells (CRL-1651) was determined using the MTT reduction assay [see ref. 6 and 7, below]. Briefly the method was as follows: HELA cells and COS-7 cells were seeded at 7.0′10³ and, respectively, 4.5′10³ cells per well and grown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. At this point, time zero (Tz) was determined by MTT reduction (see below). The supernatant of the remaining wells was discarded, and fresh medium and the peptides in serial dilutions of 12.5, 25 and 50 μM were pipetted into the wells. Each peptide concentration was assayed in triplicate. Incubation of the cells was continued for 48 hours at 37° C. at 5% CO₂. Wells were then washed once with PBS and subsequently 100 μl MTT reagent (0.5 mg/mL in medium RPMI1640 and, respectively, DMEM) was added to the wells. This was incubated at 37° C. for 2 hours and subsequently the medium was aspirated and 100 μl isopropanol was added to each well. The absorbance at 595 nm of the solubilized product was measured (OD₅₉₅peptide). For each concentration averages were calculated from triplicates. The percentage of growth was calculated as follows: (OD₅₉₅peptide-OD₅₉₅Tz-ODs₅₉₅Empty well)/(OD₅₉₅Tz-OD₅₉₅Empty well)×100% and was plotted for each peptide concentration.

The LC 50 values (Lethal. Concentration, defined as the concentration that kills 50% of the cells) were determined for each peptide by using the trend line function of EXCEL (Microsoft Office 2000) for the concentrations (50, 25, 12.5 and 0 μM), the corresponding growth percentages and the value −50, (=TREND(C50:C0,%50:%0,−50)). The GI 50 (Growth Inhibition) concentrations were calculated for each peptide by using a trend line function for the concentrations (50, 25, 12.5 and 0 μg/ml), the corresponding percentages and the value 50, (=TREND (C₅₀:C₀,%₅₀:%₀,50).

2.5. Cell Culture

‘CCR5’ cells were cultured in DMEM medium with 4500 mg/ml glucose, 10% fetal bovine serum (FBS), supplemented with 50 U/ml Penicillin and 50 Ag/ml Streptomycin (Pen/Strept.). Hut/4-3 cells were maintained in RPMI medium, 10% FBS, supplemented with Pen/Strept. and 10 mM HEPES. HELA cells and CCRF-CEM cells were maintained in RPM 11640 plus 5% FBS, Pen/Strept and 2 mM L-Glutamine. Cos-7 cells were grown in DMEM medium with 4500 mg/ml glucose supplemented with 10% FCS, Pen/Strept. and 2 mM L-Glutamine. All cell lines were grown at 37° C. at 5% CO₂. Cell media, media supplements, PBS-buffer, HEPES, Pen/Strept, L-Glutamine and sera were purchased from Gibco (Pailsey. UK). All fine chemicals came from Merck (Darmstadt, Germany).

2.6. Hemolysis

The peptides were tested for their hemolytic activity against human red blood cells (hRBC). Fresh hRBC were washed three times with phosphate buffered saline (PBS) by centrifugation for 10 min at 2000×g. Peptides at a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hour at 37° C. The final erythrocyte concentration was approximately 0.9×10⁹ cells per ml. A value of 0% resp. 100% cell lysis was determined by incubation of the hRBC in the presence of PBS alone and respectively 0.1% Triton X-100 in H₂O. The samples were centrifuged and the supernatant was 20-fold diluted in PBS buffer and the optical density (OD) of the sample at 540 nM was measured. The 100% lyses value (OD₅₄₀H₂O) gave an OD₅₄₀ of approximately 1.3-1.8. Percent hemolysis was calculated as follows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.7. Chemotactic Assay (Cell Migration Assay)

The chemotactic response of CCRF-CEM cells to a gradient of stromal cell-derived factor 1α SDF-1) was measured using disposable assay plates from Neuroprobe (5 ppore size) (Gaithersburg, Md.), according to the manufacturer's directions and references therein [especially ref. 8, below]. Briefly, one 175 cm² flask was washed once with Dubecco's phosphate buffered saline (DPBS), and trypsinized for 10 minutes or until cells had lifted. The trypsin was neutralized by the addition of fresh medium containing serum and the cells were pelleted, washed once in DPBS, and resuspended at 1-0.5×10⁷ cells/ml in RPMI+0.5% bovine serum albumin (BSA). 45 μl of cell suspension were mixed with 5 μl of 10-fold concentrated PEM peptide diluted in the same assay medium. 35 μl of this mixture were applied to the top of the assay filter. The cells were allowed to migrate (at 370) into the bottom chamber of the assay plate containing 1 nM SDF-1. After 4 hours, the filter was removed and MTT was added to the migrated cells to a final concentration of 0.5 mg/ml, and incubated for a further 4 hours. After labeling with MTT, all medium was removed and 100 μl of isopropanol+10 mM HCl were added to the cells. The optical absorbance at 595 nm (ABS₅₉₅) was read using a Tecan Genios plate reader with Magellan software. The number of cells migrated was determined by comparing ABS₅₉₅ values against a standard curve generated with a known number of cells in the assay plate and were plotted against SDF-1 concentration to obtain a sigmoidal curve and to determine the IC₅₀ values. The values for IC50 were determined using the Trendline function in Microsoft Excel by fitting a logarithmic curve to the averaged datapoints.

2.8 Plasmastability

405 μl of plasma/albumin solution were placed in a polypropylene (PP) tube and spiked with 45 μl of compound from a 100 μM solution B, derived from 135 μl of PBS and 15 μl of 1 mM peptide in PBS, pH 7.4. 150 μl aliquots were transferred into individual wells of the 10 kDa filter plate (Millipore MAPPB 1010 Biomax membrane). For “0 minutes controls”: 270 μl of PBS were placed in a PP tube and 30 μl of stock solution B was added and vortexed. 150 μl of control solution was placed into one well of the filter plate and serves as “filtered control”. Further 150 μl of control solution were placed directly into a receiver well (reserved for filtrate) and serve as “not-filtered control”. The entire plate including evaporation lid was incubated for 60 min at 37° C. Plasma samples (rat plasma: Harlan Sera lab UK, human plasma: Blutspendezentrum Züirich) were centrifuged at least for 2 h at 4300 rpm (3500 g) and 15° C. in order to yield 100 μl filtrate. For “serum albumin”-samples (freshly prepared human albumin: Sigma A-4327, rat albumin: Sigma A-6272, all at 40 mg/ml concentration in PBS) approximately 1 hour of centrifugation is sufficient. The filtrates in the receiver PP plate were analysed by LC/MS as follows: Column: Jupiter C18 (Phenomenex), mobile phases: (A) 0.1% formic acid in water and (B) acetonitrile, gradient: 5%-100% (B) in 2 minutes, electrospray ionization, MRM detection (triple quadrupole). The peak areas were determined and triplicate values are averaged. The binding is expressed in percent of the (filtered and not-filtered time point 0 min) control 1 and 2 by: 100−(100*T₆₀/T₀). The average from these values is then calculated (see ref. 9 below).

2.9. Pharmacokinetic Study (PK)

Pharmacokinetic study after single intravenous (i.v.) and intraperitoneal (i.p.) administration was performed for the compound of Example 51 (“Ex. 51”). 30 grams (±20%) male CD-1 mice obtained from Charles River Laboratories Deutschland GmbH were used in the study. The vehicle, physiological saline, was added to give a final concentration of 1 mg/ml of the compounds. The volume was 2 ml/kg i.v. and 10 ml/kg i.p and the peptide Ex. 51 was injected to give a final intraperitoneal dose of 10 mg/kg and an intravenous dose of 2 mg/kg. Approximately 250-300 μl of blood was removed under light isoflurane anesthesia from the retro-orbital plexus at predetermined time intervals (0, 5, 15, 30 min and 1, 2 and 3 hours for the i.v. study and 0, 15, 30 min and 1, 2, 4 and 8 hours for the i.p. study) and added to heparinized tubes. Plasma was removed from pelleted cells upon centrifugation and frozen at −80° C. prior to HPLC-MS analysis.

Preparation of the Plasma Calibration Samples “Blank” mouse plasma from untreated animals was used. Aliquots of plasma of 0.2 ml each were spiked with 50 ng of propranolol (Internal Standard, IS), (sample preparation by solid phase extraction on OASIS® HLB cartridges (Waters)) and with known amounts of Ex. 51 in order to obtain 9 plasma calibration samples in the range 10-5000 nM. The OASIS® HLB cartridges were conditioned with 1 ml of methanol and then with 1 ml of 1% NH₃ in water. Samples were then diluted with 700 μl of 1% NH₃ in water and loaded.

The plate was washed with 1 ml of methanol/1% NH₃ in water 5/95. Elution was performed using 1 ml of 0.1% TFA in methanol.

The plate containing eluates was introduced into the concentrator system and taken to dryness.

The residues were dissolved in 100 μL of formic acid 0.1%/acetonitrile, 95/5 (v/v) and analysed in the HPLC/MS on a reverse phase analytical column (Jupiter C 18, 50×2.0 mm, 5 μm, Phenomenex), using gradient elution (mobile phases A: 0.1% formic acid in water, B: Acetonitrile; from 5% B to 100% B in 2 min.).

Preparation of Plasma Samples

Samples coming from animal treatments were pooled in order to obtain an appropriate volume for the extraction. If the total volume obtained was less than 0.2 ml the appropriate amount of “blank” mouse plasma was added in order to keep the matrix identical to the calibration curve. Samples were than spiked with IS and processed as described for the calibration curve.

Pharmacokinetic Evaluation

PK analysis was performed on pooled data (generally n=2 or 3) using the software PK solutions 2.0™ (Summit Research Service, Montrose, Colo. 81401 USA). The area under the curve AUC was calculated by the linear trapezoidal rule. AUC_((t-∞)) was estimated as Ct/b (b: elimination rate constant). AUC_((t-∞)) is the sum of AUC_((0-t)) and AUC_((t-∞)). Elimination half-life was calculated by the linear regression on at least three data points during the elimination phase. The time intervals selected for the half-life determinations were evaluated by the correlation coefficient (r²), which should be at least above 0.85 and most optimally above 0.96. In case of i.v. administration the initial concentration at t_(zero) was determined by extrapolation of the curve through the first two time points. Finally bioavailability after i.p. administration was calculated from the normalised AUC_((0-∞)) ration after i.p. versus i.v. administration.

3.0. Results

The results of the experiments described under 2.2-2.7, above, are indicated in Table 4 herein below.

TABLE 4 Cyto- IC₅₀ (μM) FIGS ™ toxicity Hemo- Cell IC₅₀ (nM) % inhibition St. dev. LC₅₀/GI₅₀ lysis at migration Ex. Ca²⁺ assay at 200 nM at 200 nM Hela cells 100 μM assay 1 2280 n.d. n.d. 82 1.6 n.d. 2 2830 n.d. n.d. 97 0.9 n.d. 3 1000 n.d. n.d. 126 1.7 n.d. 4 2540 n.d. n.d. 191 0.7 n.d. 6 1930 n.d. n.d. 103 0.6 n.d. 20 3730 n.d. n.d. 85 0.2 n.d. 21 550 n.d. n.d. 114 0.6 n.d. 22 300 n.d. n.d. 139 0.0 n.d. 23 1550 n.d. n.d. 49 1.4 n.d. 24 850 n.d. n.d. 108 0.7 n.d. 25 1000 n.d. n.d. 108 0.0 n.d. 28 2680 n.d. n.d. 117 0.9 n.d. 31 1470 n.d. n.d. 82 0.1 n.d. 32 760 n.d. n.d. 85 0.5 n.d. 38 719.7 n.d. n.d. 348 0.3 n.d. 45 n.d. 65.1 4.8 132 0.4 n.d. 51 1.9 93.9 1.0 97 0.0  0.275 52 3.1 95.4 1.3 99 0.0 2.75 53 57.8 91.8 1.6 86 0.2 n.d. 54 6.9 n.d. n.d. 54 0.0 n.d. 55 6.3 n.d. n.d. 43 0.1 n.d. 56 0.74 n.d. n.d. 60 — n.d. 57 4.2 n.d. n.d. 33 0.1 n.d. 58 10.5 n.d. n.d. 18 0.0 n.d. 59 7.8 n.d. n.d. 33 0.1 n.d. 60 0.18 n.d. n.d. 62 0.1 n.d. 61 4.1 n.d. n.d. >100 0.3 n.d. 62 1.8 n.d. n.d. 65 0.1 n.d. 63 2.0 n.d. n.d. 58 0.2 n.d. 64 3.3 n.d. n.d. 66 0.3 n.d. 65 3.9 n.d. n.d. 65 0.2 n.d. 66 3.8 n.d. n.d. 46 0.0 n.d. 67 2.4 n.d. n.d. 49 0.2 n.d. 68 1.1 n.d. n.d. >100 0.1 n.d. 69 1.8 n.d. n.d. 49 0.1 n.d. 70 19.5 n.d. n.d. 40 0.2 n.d. 71 2.7 n.d. n.d. 34 0.1 n.d. 72 3.9 n.d. n.d. 36 0.5 n.d. 73 8.8 n.d. n.d. 20 0.3 n.d. 74 19.5 n.d. n.d. 40 0.4 n.d. 75 3.5 n.d. n.d. >100 0.0 n.d. 76 5.6 n.d. n.d. >100 0.1 n.d. 77 7 n.d. n.d. >100 0.2 n.d. 78 11 n.d. n.d. 69 0.1 n.d. 79 2.4 n.d. n.d. 94 0.0 n.d. 80 2.9 n.d. n.d. 44 0.1 n.d. 81 4.9 n.d. n.d. 45 0.0 n.d. 82 4.8 n.d. n.d. 40 0.0 n.d. 83 3.7 n.d. n.d. 48 0.1 n.d. 84 3.9 n.d. n.d. 62 0.0 n.d. 85 2.7 n.d. n.d. 94 0.0 n.d. 86 0.69 n.d. n.d. 62 0.0 n.d. 87 3.5 n.d. n.d. 64 0.0 n.d. 88 2.5 n.d. n.d. 44 0.0 n.d. 89 0.5 n.d. n.d. 50 0.0 n.d. 90 19.5 n.d. n.d. 57 0.1 n.d. 91 2.1 n.d. n.d. 48 0.2 n.d. 92 1.1 n.d. n.d. 53 0.5 n.d. 93 4.3 n.d. n.d. >100 0.2 n.d. Cyto- IC₅₀ (μM) FIGS ™ toxicity Hemo- Cell IC₅₀ (nM) % inhibition St. dev. GI₅₀ lysis at migration Ex. Ca²⁺ assay at 200 nM at 200 nM Hela cells 100 μM assay 94 2.5 n.d. n.d. 45 0.2 n.d. 95 2.9 n.d. n.d. 41 0.1 n.d. 96 3.0 n.d. n.d. 69 1.0 n.d. 97 4.3 n.d. n.d. 44 0.8 n.d. 98 3.9 n.d. n.d. 41 1.0 n.d. 99 4.2 n.d. n.d. 40 1.1 n.d. 100 7.0 n.d. n.d. 43 0.8 n.d. 101 1.28 n.d. n.d. 74 0.6 n.d. 102 8.0 n.d. n.d. 33 0.5 n.d. 103 18.3 n.d. n.d. 42 0.2 n.d. 104 7.4 n.d. n.d. 71 0.0 n.d. 105 0.62 n.d. n.d. 49 0.0 n.d. 106 3.1 n.d. n.d. 83 0.0 n.d. 107 3.8 n.d. n.d. 50 0.4 n.d. 108 4.6 n.d. n.d. 70 0.0 n.d. 109 3.0 n.d. n.d. 65 0.0 n.d. 110 1.7 n.d. n.d. 48 0.0 n.d. 111 1.6 n.d. n.d. >100 0.0 n.d. 112 7.8 n.d. n.d. 76 0.0 n.d. 113 0.62 n.d. n.d. 45 0.0 n.d. 114 1.3 n.d. n.d. 67 0.0 n.d. 115 2.7 n.d. n.d. >100 0.1 n.d. 116 14.5 n.d. n.d. 20 0.0 n.d. 117 3.4 n.d. n.d. 44 0.0 n.d. 118 7.6 n.d. n.d. 52 0.0 n.d. 119 9.4 n.d. n.d. 63 0.0 n.d. 120 8.1 n.d. n.d. 78 0.0 n.d. 121 6.5 n.d. n.d. 79 0.0 n.d. 122 8.8 n.d. n.d. 60 0.0 n.d. 123 10.0 n.d. n.d. 80 0.0 n.d. 124 5.9 n.d. n.d. 21 0.0 n.d. 125 330.0 n.d. n.d. >100 0.0 n.d. 126 19.5 n.d. n.d. 85 0.0 n.d. 127 52.2 n.d. n.d. 62 0.0 n.d. 128 4.5 n.d. n.d. 43 0.0 n.d. 129 10.9 n.d. n.d. 23 0.0 n.d. 130 4.1 n.d. n.d. 62 0.0 n.d. 131 2.4 n.d. n.d. 53 0.0 n.d. 132 1.9 n.d. n.d. 76 0.0 n.d. 133 5.3 n.d. n.d. 45 0.1 n.d. 134 1.7 n.d. n.d. 21 0.0 n.d. 135 4.7 n.d. n.d. 30 0.1 n.d. 136 4.1 n.d. n.d. >100 0.0 n.d. 137 1.28 n.d. n.d. 79 0.5 n.d. 138 63.0 n.d. n.d. 18 0.0 n.d. 140 19.6 n.d. n.d. 35 0.0 n.d. 141 >10 n.d. n.d. 18 n.d. n.d. 142 96.9 n.d. n.d. n.d. n.d. n.d. 143 0.9 n.d. n.d. 46 n.d. n.d. 144 0.18 n.d. n.d. n.d. n.d. n.d. 145 0.38 n.d. n.d. 97 0.0 n.d. 146 0.24 n.d. n.d. n.d. n.d. n.d. 147 0.17 n.d. n.d. n.d. n.d. n.d. 148 0.65 n.d. n.d. 46 71   n.d. 149 1.0 n.d. n.d. >100 0.0 n.d. 150 1.4 n.d. n.d. n.d. n.d. n.d. 151 4.2 n.d. n.d. 83 0.9 n.d. 152 4.2 n.d. n.d. 46 0.0 n.d. 153 21.9 n.d. n.d. 43 1.7 n.d. 154 9.3 n.d. n.d. n.d. n.d. n.d. 155 0.46 n.d. n.d. n.d. n.d. n.d. 156 49 n.d. n.d. n.d. n.d. n.d. 157 11.3 n.d. n.d. n.d. n.d. n.d. 158 250 n.d. n.d. n.d. n.d. n.d. 159 118 n.d. n.d. n.d. n.d. n.d. 160 0.38 n.d. n.d. n.d. n.d. n.d. n.d.: not determined

The determination of IC50 (nM) values in the Ca2+ assay for Ex. 1-53 was performed using method 1, for Ex. 54-155 method 2 was used. For the determination of cytotoxicity values in Ex. 1-53 the LC50 calculation was used, for Ex. 52-160 the GI50 calculation was used.

The determination of IC50 (nM) values in the Ca2+ assay for Ex. 1-53 was performed using method 1, for Ex. 54-160 method 2 was used.

The results of the experiment described in 2.8, above, are indicated in Table 5 herein below.

TABLE 5 Ex. Stability human Plasma t_(1/2) (min) Stability rat Plasma t_(1/2) (min) 51 286 >300 60 >300 >300 61 273 >300 68 127 81 75 188 142 85 166 >300 101 >300 247 102 255 245 110 115 259 124 >300 >300 120 39 174 151 89 71 152 23 86

The results of the experiment described in 2.9 (PK), above, are indicated in Tables 6, 7 and 8 herein below.

TABLE 6 Route i.v. Dose 2 mg/kg n. of Time Calc. Conc animals (h.) (ng/ml) pooled 0.083 1461 3 0.25 328 2 0.5 300 3 1 80 3 2 68 3 3 49 3

TABLE 7 Route i.p. Dose 10 mg/kg n. of Time Calc. Conc animals (h.) (ng/ml) pooled 0.25 673 3 0.5 1568 2 1 2009 2 2 3160 2 4 1024 3 8 519 3

TABLE 8 Administration route Intravenous Intraperitoneal Dose (mg/kg) 2 10 AUC_(0-t) (ng · h/ml) 1704 11112 AUC_(0-inf.) (ng · h/ml) 1905 12948 AUC_(norm.) (ng · h/ml) 953 1295 C_(max) ng/ml 28594 3160 C_(max norm.) 14297 316 T_(max) (hour) 0 2 β (hours⁻¹) 0.24 0.28 Half-life (hours) 2.8 2.5 % absorbed (F) (percentage of 100 136 normalized AUC_(0-inf.) intraperitoneal against normalized AUC_(0-inf) i.v.)

After intravenous administration of Ex. 51 at a dose level of 2 mg/kg body weight. Ex. 51 followed intravenous kinetic characteristics. After PK analysis, Ex. 51 showed an extrapolated C_(initial) of 28594 ng/ml and a C_(max) observed of 1461 ng/ml at 5 min. Plasma levels rapidly decreased to 328 and 80 ng/ml at 15 min and 1 hour respectively. From 1 to 3 h plasma levels decreased with an elimination half-life of 2.8 h to 49 ng/ml at 3 h.

The AUC_((0-t)) and AUC_((0-∞)) amounted to 1704 and 1905 ng·h/ml, respectively. After intraperitoneal administration of Ex. 51 at a dose level of 10 mg/kg body weight, plasma levels of Ex. 51 increased almost linearly within the first 2 h and showed a C_(max) of 3160 ng/ml at 2 hours. From 2 to 8 h plasma levels decreased with an elimination half-life of 2.5 h to 519 ng/ml at 8 h. The AUC_((0-t)) and AUC_((0-∞)) amounted to 11112 and 12948 ng·h/ml, respectively. As compared to the normalized AUC value after i.v. administration (100% absorbed, 953 ng·h/ml) of Ex. 51 absorbed after i.p. administration amounted to 136% (1295 ng·h/ml) at an 45 times lower normalised Cmaxafter i.p. administration (316 versus 1497 ng/ml). The value above 100% may partially reflect an impaired reliability caused by the limited number of points.

REFERENCES

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The invention claimed is:
 1. A compound of the general formula

is a dipeptide residue made up of two different amino acid building blocks, the dipeptide being ^(D)Pro-^(L)Pro; and Z is a chain made up of 12 α-amino acid residues, in which the P1 residue is the residue of Tyr; the P2 residue is the residue of Arg or Gly; the P3 residue is the residue of Cit; the P4 residue is the residue of Val, Phe, Cys, Gly, Ile, Thr or Gln; the P5 residue is the residue of Arg; the P6 residue is the residue of ^(D)Arg or Arg; the P7 residue is the residue of Arg; the P8 residue is the residue of 2-Nal or Trp; the P9 residue is the residue of Phe, Val, Cys, Gly, Ile, Thr or Gln; the P10 residue is the residue of Tyr; the P11 residue is the residue of Cit or Gly; the P12 residue is the residue of Lys; when P4 and P9 are both cysteine, a disulfide bridge is present between the two side chains thereof; or an enantiomer of said compound, or a pharmaceutically acceptable salt of said compound.
 2. A An enantiomer of a compound of claim
 1. 3. A compound according to claim 1 having CXCR4 antagonizing activity, which also has anticancer activity and/or anti-inflammatory activity, wherein the cancer is selected from the group consisting of breast cancer, brain cancer, prostate cancer, lung cancer, kidney cancer, neuroblastoma, non-hodgkin's lymphoma, ovarian cancer, multiple myeloma, chronic lymphocytic leukemia, pancreatic cancer, melanoma, and whereas the inflammatory activity is selected from the group consisting of asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing sponylitis, systemic sclerosis, Sjogren's syndrome, systemic anaphylaxis or hypersensitivity responses, drug allergies, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection including allograft rejection or graft-versus-host disease, inflammatory bowel diseases and inflammatory dermatoses.
 4. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically inert carrier.
 5. A composition according to claim 4 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration.
 6. A composition according to claim 4 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories.
 7. A method of antagonizing CXCR4 in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim
 1. 8. The method according to claim 7 wherein said antagonism of CXCR4 is intended to be for slowing viral progression in infected patients.
 9. A process for the manufacture of a compound according to claim 1 which process comprises (a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the end-product is in position 8, 9 or 10, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (b) removing the N-protecting group from the product thus obtained; (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d) removing the N-protecting group from the product thus obtained; (e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced; (f) coupling the product thus obtained with a compound of the general formula

is as defined in claim 1 and X is an N-protecting group (g) removing the N-protecting group from the product obtained in step (f); (h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (i) removing the N-protecting group from the product thus obtained; (j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (k) removing the N-protecting group from the product thus obtained; (l) repeating steps (j) and (k) until all amino acid residues have been introduced; (m) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated; (n) optionally, forming one, two or three interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the chain of 12 α-amino acid residues; (o) detaching the product thus obtained from the solid support; (p) cyclizing the product cleaved from the solid support; (q) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and (r) optionally converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.
 10. A process for the manufacture of a compound according to claim 1 which process comprises (a′) coupling an appropriately functionalized solid support with a compound of the general formula

is as defined above and X is an N-protecting group (b′) removing the N-protecting group from the product obtained in step (a′); (c′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d′) removing the N-protecting group from the product thus obtained; (e′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (f′) removing the N-protecting group from the product thus obtained; (g′) repeating steps (e′) and (f′) until all amino acid residues have been introduced; (h′) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated; (i′) optionally, forming one, two or three interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the chain of 12 α-amino acid residues; (j′) detaching the product thus obtained from the solid support; (k′) cyclizing the product cleaved from the solid support; (l′) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and (m′) optionally, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.
 11. The process according to claim 9 wherein the process is modified for the manufacture of enantiomers of the compounds in which enantiomers of all chiral starting materials are used.
 12. A The process according to claim 10 wherein the process is modified for the manufacture of enantiomers of the compounds in which enantiomers of all chiral starting materials are used. 